Acta Neuropathol (2013) 125:47–75

DOI 10.1007/s00401-012-1057-6

REVIEW

Desminopathies: pathology and mechanisms

Christoph S. Clemen • Harald Herrmann •

Sergei V. Strelkov • Rolf Schröder

Received: 22 September 2012 / Revised: 15 October 2012 / Accepted: 18 October 2012 / Published online: 11 November 2012
Ó The Author(s) 2012. This article is published with open access at Springerlink.com

Abstract The intermediate filament protein desmin is an changes of the myofibrillar apparatus. The molecular
essential component of the extra-sarcomeric cytoskeleton in pathophysiology of desminopathies is a complex, multi-
muscle cells. This three-dimensional filamentous frame- level issue. In addition to direct effects on the formation and
work exerts central roles in the structural and functional maintenance of the extra-sarcomeric intermediate filament
alignment and anchorage of myofibrils, the positioning of network, mutant desmin affects essential protein interac-
cell organelles and signaling events. Mutations of the tions, cell signaling cascades, mitochondrial functions, and
human desmin gene on chromosome 2q35 cause autosomal protein quality control mechanisms. This review summa-
dominant, autosomal recessive, and sporadic myopathies rizes the currently available data on the epidemiology,
and/or cardiomyopathies with marked phenotypic vari- clinical phenotypes, myopathology, and genetics of des-
ability. The disease onset ranges from childhood to late minopathies. In addition, this work provides an overview on
adulthood. The clinical course is progressive and no spe- the expression, filament formation processes, biomechani-
cific treatment is currently available for this severely cal properties, post-translational modifications, interaction
disabling disease. The muscle pathology is characterized partners, subcellular localization, and functions of wild-
by desmin-positive protein aggregates and degenerative type and mutant desmin as well as desmin-related cell and
animal models.

Keywords Desmin  Desminopathy 

C. S. Clemen (&)
Institute of Biochemistry I, Medical Faculty, University Intermediate filaments  Myofibrillar myopathy 
of Cologne, Joseph-Stelzmann-Street 52, Protein aggregate myopathy
50931 Cologne, Germany
e-mail: [email protected]

H. Herrmann Abbreviations
Functional Architecture of the Cell, German Cancer Research APEG1 Aortic preferentially expressed protein 1
Center (DKFZ), Im Neuenheimer Feld 580, (synonym: SPEG)
69120 Heidelberg, Germany
BAG-3 BAG family molecular chaperone regulator 3
e-mail: [email protected]
BLOC-1 Biogenesis of lysosome-related organelles
S. V. Strelkov complex 1
Laboratory for Biocrystallography, Department CCD Cardiac conduction defects
of Pharmaceutical and Pharmacological Sciences,
CHPF Chondroitin sulfate synthase 2
Katholieke Universiteit Leuven, O&N II Herestraat 49,
Box 822, 3000 Leuven, Belgium CK Kreatine kinase
e-mail: [email protected] COX Cytochome c oxidase
DES Desmin gene
R. Schröder (&)
DNAJB6 DnaJ homolog subfamily B member 6
Institute of Neuropathology, University Hospital Erlangen,
Schwabachanlage 6, 91054 Erlangen, Germany (synonym: heat shock protein J2)
e-mail: [email protected] ECG Electrocardiogram

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EMG Electromyography pathways leading from an individual MFM gene defect to a

FHL1 Four and a half LIM domains protein 1 shared myopathological disease manifestation are still
GFAP Glial fibrillary acidic protein unclear.
GT Gomori trichrome Desmin is a member of the intermediate filament (IF)
H&E Hematoxylin and eosin protein gene family, which comprises 70 members [78]. Up
Hsp Heat shock protein to now, the IF gene family represents one of the most
IF Intermediate filament highly mutated groups of related genes in the human
LCR 50 locus control region genome, accounting for at least 94 different disease entities
MEF Mouse embryonic fibroblast [132, 176]. IF proteins are expressed in a tissue- and
MFM Myofibrillar myopathy development-specific manner, e.g., keratins in epithelial
mrf4 Muscle-specific regulatory factor 4 tissues, GFAP in astrocytes, and neurofilament proteins in
(synonym: myf-6) neurons. As a particular unique property, the IF gene
MRI Magnetic resonance imaging family harbors three genes that code for proteins localizing
myf-6 Myogenic factor 6 (synonym: mrf4) to the nuclear envelope within the cell nucleus, i.e., lamin
myoD Myoblast determination protein 1 A and its smaller splice form lamin C, lamin B1, and lamin
NADH-TR Reduced nicotinamide adenine dinucleotide B2. According to the degree of sequence identity, IF pro-
tetrazolium reductase teins have been grouped into six sequence homology
PA28 Proteasome activator 28 (synonym PSME) classes (SHC): acidic keratins (SHC I); basic keratins (SHC
PAS Periodic acid Schiff II); desmin, vimentin and other mesenchymal IF proteins
PSME Proteasome activator complex subunit such as GFAP (SHC III); neurofilament proteins (SHC IV);
(synonym: PA28) lamins (SHC V); and an orphan group harboring the lens-
SDH Succinic dehydrogenase specific IF proteins phakinin and filensin [72]. Human IF-
SDS-PAGE Sodium dodecyl sulfate polyacrylamide gel related diseases range from skin blistering (keratins),
electrophoresis Alexander’s disease (GFAP), Charcot-Marie-Tooth disease
SHC Sequence homology class (neurofilament proteins), and Hutchinson-Gilbert progeria
SPEG Striated muscle preferentially expressed (lamin A/C) to cataracts (phakinin). Notably, and subject of
protein kinase this review, mutations of desmin, the major class III IF
ULF Unit length filament protein in striated and smooth muscle cells, causes pro-
VCP Valosin containing protein gressive myopathy, cardiomyopathy, cardiac conduction
XLCNM X-linked centronuclear myopathy defects, and arrhythmias [160, 183]. Information on the
ZASP Z-band alternatively spliced PDZ-motif expression, localization, interaction, and function of IFs in
protein (synonyms: cypher, LIM domain- general and desmin in particular is a prerequisite for the
binding protein 3) understanding of human desminopathies. In the present
article we will summarize the essential data on desmin and
desminopathies derived from numerous clinical and
molecular studies.
General introduction

Desminopathies (synonyms: desmin-related myopathy, Clinical phenotypes

desmin myopathy, desmin storage myopathy, and others
[166]) belong to the clinically and genetically heteroge- Epidemiology
neous group of myofibrillar myopathies (MFM), which are
morphologically characterized by the presence of desmin- Since detailed epidemiological studies on MFM are not
positive protein aggregates and degenerative changes of the available, the incidence and prevalence of desmin myop-
myofibrillar apparatus [160, 164]. Since the first descrip- athy and/or cardiomyopathy are currently unclear.
tion of desmin and aB-crystallin mutations causing MFM Interpretation of the thus far published data allows the
in 1998 [58, 187], an increasing number of MFM disease assumption that desminopathies fulfill the definition of a
genes coding for sarcomeric and extra-sarcomeric proteins, rare disease with no more than 5 affected individuals in
i.e., BAG-3, FHL1, filamin-C, myotilin, plectin, titin, and 10,000. In a study on the prevalence of desmin mutations in
ZASP, have been identified [126, 138, 160, 164]. In addi- a cohort of 116 families and 309 additional patients with
tion, protein aggregate myopathies due to mutations in the pure dilatative cardiomyopathy, desmin mutations
DNAJB6 and VCP genes share part of their morphological accounted for up to 2 % of disease manifestation [178].
features with MFM [84, 151]. The precise molecular Desmin mutations also seem to be one of the more

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frequently encountered gene defects in the MFM group. In and peroneal muscles are early and predominant signs of
a cohort of 53 patients from 35 Spanish MFM families, desminopathies [48, 156].
myotilin mutations were the predominant cause affecting
18 families followed by desmin mutations in 11 families Cardiac disease
[130]. In earlier studies reporting on the Mayo MFM cohort
of 63 patients, 6 carried myotilin and 4 carried desmin Cardiac disease manifestations in desminopathies, which
mutations [165, 166]. Desminopathies have been reported may precede, coincide with, or succeed skeletal muscle
in diverse ethnic groups and affect both female and male weakness, comprise true cardiomyopathy as well as various
patients. Gender effects have been reported in two studies, forms of cardiac conduction defects (CCD) and arrhyth-
in which male heterozygous mutation carriers were more mias [92, 173, 178, 183, 185]. The above-cited meta-
prone to cardiac disease manifestations [5, 183]. The dis- analysis revealed the presence of cardiological signs in
ease manifestation is highly variable with an age of onset 74 % (105/141) of desmin mutation carriers [183]. Isolated
ranging from the 1st to the 8th decade of life. In rare cardiological signs were reported in 22 % (34/152) of
recessive forms the disease manifests in the 1st decade of carriers. Out of 67 patients with verified cardiomyopathy
life [31, 58, 121, 140]. In the more frequently encountered (49 %; 67/138), 23 were classified as dilatative, 18 as
familial and sporadic cases due to heterozygous desmin unspecified, 16 as restrictive, 8 as hypertrophic, and 2 as
mutations, a disease onset ranging from the 2nd to the 4th arrhythmogenic right ventricular cardiomyopathy. Desmin
decade of life has been reported in the majority of patients mutations frequently lead to clinically symptomatic and
[160, 183]. asymptomatic ECG abnormalities (62 %; 83/133). In this
group, CCD seems far more frequent (39 %; 52/133) than
Skeletal muscle disease isolated arrhythmias (5 %; 6/133). A combination of both
was found in 19 % (25/133) of carriers. A more detailed
Initially, desminopathies have been associated with a pro- characterization of 77 patients with CCD revealed that
gressive distal myopathy phenotype starting in the lower atrioventricular block (47) and right bundle branch block
legs. However, subsequent studies reported the association (14) were the most prevalent manifestations. In 31 patients
between desmin mutations and limb girdle, scapulopero- with arrhythmias, atrial fibrillation (9), ventricular pre-
neal, and generalized myopathy phenotypes [9, 35, 191]. A mature beats (8), and ventricular tachycardia (7) were the
meta-analysis based on the interpretation of published data most frequently detected ECG abnormalities. Thus, a basic
from 159 patients carrying 40 different heterozygous des- electrophysiological workup should include a 12-lead sur-
min mutations provided highly valuable insights into this face ECG and a 24-h Holter ECG. The cardiac function is
complex issue [183]. Signs of combined distal and proxi- routinely assessed by transthoracic echocardiography.
mal muscular weakness were found in two thirds (67 %; However, cardiac MRI has been proposed as a more sen-
71/106) of mutation carriers, whereas true distal and sitive diagnostic tool to detect focal cardiac pathology in
proximal myopathy phenotypes were only present in 27 % early and clinically asymptomatic stages of desminopathy
(29/106) and 6 % (6/106), respectively. In this study, 74 % [173].
(110/148) of carriers had signs of skeletal muscle disease.
Isolated skeletal muscle disease was reported in 22 % (31/
141) of carriers. A combination of signs of skeletal muscle Pulmonary and miscellaneous disease manifestations
and cardiac pathology was found in 49 % (67/137).
Creatine kinase (CK) levels in desmin mutation carriers Patients with desmin mutations are at risk to develop
are of limited diagnostic value; 57 % (62/109) of mutation respiratory problems. In the desminopathy meta-analysis
carriers had elevated CK levels (91 % displayed a B4-fold 26 % (29/110) of carriers were reported to suffer from
increase). Remarkably, 30 % (25/83) of patients with respiratory insufficiency [183]. Thus, blood gas analysis
manifest skeletal muscle disease were reported to have and spirometry are mandatory in patients with desminop-
normal CK levels [183]. Needle electromyography (EMG) athies. Cataracts, swallowing difficulties, intestinal pseudo-
typically reveals a myopathic pattern with short duration, obstruction, and repetitive episodes of diarrhea and
polyphasic, and low amplitude motor unit potentials. In constipation have been reported as miscellaneous or puta-
addition, positive sharp waves, fibrillation potentials, and tive disease-related symptoms [6, 58, 129, 183].
pseudomyotonic/myotonic discharges have frequently been
documented in desminopathy patients [160]. Sensory and Disease progression and mortality
motor nerve conduction studies usually give normal results
[59]. Muscle MRI studies pointed out that signal alterations Desmin myopathies and cardiomyopathies are character-
in the gluteus maximus, semitendinosus, sartorius, gracilis, ized by a progressive course and may change their initial

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clinical presentation. In a case report, the transformation of

an initially hypertrophic cardiomyopathy into a restrictive
and finally dilated cardiomyopathy has been documented
[65]. A further study reported on a 10-year follow-up of 28
patients from 19 families with desmin mutations [190]. In
11 patients, primary skeletal muscle involvement was fol-
lowed by cardiac disease after 6.3 ± 3.5 years, whereas in
16 patients with a primary cardiac disease manifestation
skeletal muscle problems occurred after 6.8 ± 4.1 years.
Out of the latter group, six patients presented with major
cardiac complications. A progression from mild conduction
defects to high degree conduction blocks requiring per-
manent pacing was observed in 8 out of 19 patients. In this
cohort of 28 patients, 5 died at a mean age of
58.0 ± 6.5 years, accounting for a mortality rate of 17.8 %
[190]. In the desminopathy meta-analysis, however, a
mortality rate of 26 % (27/104) of desmin mutation carriers
with a mean age 49 ± 9.3 years was reported [183].
Documented causes of death in both studies were sudden
cardiac death, heart failure, respiratory insufficiency, chest
infection, and iatrogenic complications of cardiac treat-
ment. Both studies conclusively underline that the cardiac
disease manifestation is the major cause of premature death
in desminopathies.

Muscle biopsy findings

Light microscopy

Diagnostic skeletal muscle biopsies from patients with

desminopathies usually show mild to severe signs of a
degenerative myopathy with rounding of muscle fibers,
fiber splitting, internalization of myonuclei, and increased
connective and fat tissue. Pathological protein aggregates,
the hallmark of MFM, generally emerge as subsarco-
Fig. 1 Protein aggregation pathology and mitochondrial abnormali-
lemmal and/or sarcoplasmic inclusions. In addition, ties in desminopathies. Arrows and double arrows in a and b denote
sarcoplasmic bodies as well as rimmed and non-rimmed pathological protein aggregates in the sarcoplasm and in the
vacuoles may be present. The typical pathology of MFM subsarcolemmal region, respectively. Arrowhead and double arrow-
head in c highlight a rubbed-out lesion and a core-like lesion,
is best visualized in H&E and modified Gomori trichrome
respectively
(GT) stains (Fig. 1a, b). Enzymatic stains (NADH-TR,
SDH, and COX) may show further characteristic oxidative
enzyme and mitochondrial abnormalities comprising Immunodetection
rubbed-out fibers and core-like lesions (Fig. 1c). The stage
of disease progression in individual muscles often mirrors Desmin immunostaining is mandatory to depict desmin-
the severity of the observed myopathological changes. positive pathological protein aggregates in the subsarco-
However, one should keep in mind that the myopatho- lemmal and/or sarcoplasmic region. In addition to the
logical picture of desminopathies is highly variable. The characteristic immunoreactivity to desmin (Fig. 2a), the
myopathological findings in genetically proven desmin- pathological protein aggregates are positively stained by a
opathies range from no overt pathology over subtle wide variety of antibodies directed against cytoskeletal
myopathic changes with or without pathological protein proteins (e.g., dystrophin, F-actin, filamin C, myotilin,
aggregates to the picture of a vacuolar myopathy [35, 160, plectin, synemin), heat shock proteins (e.g., aB-crystallin,
161]. Hsp27), ubiquitin, Alzheimer-related proteins (e.g., b-APP),

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Fig. 2 Indirect immunofluorescence labeling of desmin and aB-

crystallin in a desminopathy. Note the presence of sarcoplasmic and
subsarcolemmal pathological protein aggregates

Fig. 3 Electron microscopy findings in desminopathies. Asterisks

and cyclin-dependent kinases (e.g., CDK2, p21). Out of denote the presence of granulofilamentous material in the subsarco-
lemmal region. White arrows depict electron-dense granular deposits;
this long list, stains for aB-crystallin (Fig. 2b), filamin-C, black arrows highlight filamentous material. ECM extracellular
and myotilin are sensitive diagnostic tools to depict path- matrix, M mitochondrion
ological protein aggregation in desminopathies and other
forms of MFM [161, 166]. Cardiac pathology

Electron microscopy Desmin-positive protein aggregates as well as granulofila-

mentous and electron-dense amorphous materials are also
Granulofilamentous material in the subsarcolemmal region the morphological hallmarks of desmin cardiomyopathies.
and/or between neighboring myofibrils is the classical Pathological aggregates have been demonstrated in sub-
ultrastructural hallmark of desminopathies (Fig. 3). sarcolemmal, intermyofibrillar, and perinuclear regions.
However, granulofilamentous material is not specific for Further reported pathological findings were myocyte
this disease entity as it has been described in other forms hypertrophy, disarray of the myocytes, mis-shaped
of MFM, in particular in aB crystallinopathies. Other myonuclei, cytoplasmic vacuolar degeneration, focally
features of pathological protein aggregation are cyto- lysed myofibrils, various degrees of diffuse interstitial
plasmic bodies and autophagic vacuoles. These changes fibrosis, and mitochondrial abnormalities [3, 4, 20]. With
are found in conjunction with signs of myofibrillar respect to CDC and arrhythmias, pathological changes
degeneration comprising Z-disc alterations (streaming, were noted in the cardiac conduction system of two
irregularities, loss, and rods), myofibrillar remnants, and autopsy cases. In one, calcifications at the bundle of His
core and core-like lesions. Typical signs of concomitant and calcium deposits at the left and right bundle branches
mitochondrial pathology are areas with accumulation or were noted [199], whereas in the other extensive fibrosis in
depletion of mitochondria with normal or abnormal the terminal portion of the branching bundle and the initial
morphology. segments of the left and right bundles were described [20].

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The shape of intercalated discs has been reported to be currently available information on the epigenetic regula-
abnormal with convoluted, elongated, and zigzag patterns tion of DES is still limited. The DES promoter contains a
[185]. Furthermore, decreased immunoreactivities of the CpG-island also covering the DES transcription start site
desmosomal proteins desmoplakin and plakophilin-2 and and exon 1. It has been described that the DES promoter
the ventricular gap junctional protein connexin-43 have is non-methylated regardless of its expression status. The
been described [133]. Remarkably, smooth muscle cells of expression of desmin in muscle cells seems to be acti-
cardiac blood vessels seem not to contain desmin-positive vated by acetylation of histones H3 and H4 as well as
aggregates [4]. As in skeletal muscle biopsy, the extent of methylation of histone H3 at lysine residue 4 (H3K4me2
typical pathology is highly variable in cardiac specimens and me3) around the transcription start site of DES. In
from desminopathies. non-muscle cells, the DES promoter is silenced by
methylation of histone H3 lysine residue 27 (H3K27me3)
[108].
Differential diagnosis
Desmin mutation spectrum
The differential diagnosis of desminopathies is complex
and depends on the initial clinical disease presentation. Disease-causing mutations spread over the entire DES
Patients with a highly indicative phenotype of desminop- gene. They significantly cluster in exon 6, which encodes
athy (combined skeletal muscle and cardiac symptoms, no the C-terminal half of the coil 2 domain (Fig. 4). Mutations
extra-muscular signs, autosomal dominant inheritance, in this domain have primarily been associated with a
disease onset between the 2nd and 4th decade of life) skeletal muscle phenotype, whereas mutations residing in
represent only a minority. In cases with isolated cardiac the head and tail domains of the desmin protein seem more
problems, a broad spectrum of acquired and hereditary frequently associated with a cardiac phenotype [183]. As of
conditions has to be taken into consideration. In cases of June 2012, 67 disease-causing mutations of the DES gene
progressive skeletal muscle weakness without cardiac have been published. These mutations may lead to the
involvement, the differential diagnosis ranges from pri- expression of 61 different mutant forms of desmin
mary distal myopathies, limb girdle muscular dystrophies, (Table 1).
and scapuloperoneal syndromes to generalized myopathies.
A diagnostic muscle biopsy in these cases often provides Autosomal dominant inheritance
the first clue to the diagnosis of MFM. Careful interpreta-
tion of the clinical data, including sex, age of onset, mode The vast majority of familial desminopathies follow an
of inheritance, and presence or absence of extramuscular autosomal dominant mode of inheritance. The most fre-
signs such as cataracts (aB-crystallinopathy), early respi- quent DES mutations are missense mutations leading to
ratory failure (titinopathy), blistering skin (plectinopathy), single amino acid substitutions. Splice site mutations
and rigid spine and scoliosis (FHL1opathy, BAG-3opathy) causing the loss of exon 3 (p.Asp214_Glu245del), small
is essential to differentiate specific MFM subtypes. In in-frame deletions of one, three or seven codons, and frame
MFM patients with a disease onset beyond the 4th decade shift mutations, which may lead to the expression of
of life, mutations in genes coding for myotilin, ZASP, and truncated desmin protein species, have been reported only
filamin-C should initially be considered [160, 164]. in a small number of patients (Table 1). For the
p.Arg350Pro mutation, the most frequently encountered
pathogenic desmin missense mutation in Germany, a
Genetics of desminopathies founder allele has been established [191].

Human desmin gene Autosomal recessive inheritance

The human desmin gene (DES) on chromosome 2q35 is a Five families with an autosomal recessive mode of inher-
single copy gene that spans over a length of approximately itance have been published thus far. In one family, the
8.3 kb and comprises nine exons coding for a 470-amino homozygous Arg16Cys missense mutation was observed
acid protein with a molecular weight of 53.5 kDa [106]. [4]. In two families, a small in-frame deletion has been
DES belongs to a gene cluster further comprising APEG1 identified leading to p.Arg173_Glu179del [121, 140]. In
(synonym SPEG or striated muscle preferentially expressed another family, a 22 base pair deletion in exon 6 causing a
protein kinase) and CHPF. This gene cluster is most likely premature stop codon associated with a virtually complete
regulated by the DES 50 locus control region (LCR), which lack of desmin protein has been reported [31]. In the fifth
has been identified 9–18 kb upstream of DES [177]. The family, the disease manifestation has been attributed to a

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Fig. 4 Structural organization of the human desmin molecule and the corresponding vimentin domain [33]. The three a-helical
molecular model of its dimeric rod domain. a The black boxes segments (coil 1A, coil 1B and coil 2) are shown as black ribbons.
represent a-helical segments designated ‘‘coil.’’ Segments of The linkers L1 and L12 are in grey. The first segment (coil 1A) has
unknown structure connecting coil 1A and coil 1B as well as coil only a weak tendency to form coiled coils [33]. Locations of
1B and coil 2 are termed linkers L1 and L12, respectively. Non- pathogenic mutations are mapped in orange (missense mutations),
structured amino- (‘‘head’’) and carboxy- (‘‘tail’’) terminal domains purple (deletions), and cyan (truncations). For clarity, mutation sites
are depicted as colored bars. Numbers indicate the amino acid in only one chain of the dimer are marked. The mutations within the
position of the domain borders. b The molecular model of the dimeric unstructured head and tail domains are also listed; see also Table 1
desmin coiled coil domain is based on its high structural homology to

compound heterozygote DES mutation (p.Ala360Pro/ structural model of desmin is derived from recent structural
p.Asn393Ile [58]) (Table 1). analyses of the closely related class III IF protein vimentin
[33] (Fig. 4b). Coil 1 consists of two a-helical subdomains,
Sporadic forms i.e., coil 1A and coil 1B. They are separated by linker L1,
which could also accommodate a-helical conformation.
In addition to these familial cases, an increasing number of While coil 1B forms a stable dimeric coiled coil, the coil
sporadic desminopathies have been published. These spo- 1A segment has only a weak coiled-coil forming capacity.
radic disease manifestations are due to missense, splice In addition, the current model omits the previously used
site, or frame-shift mutations (Table 1). separation into coil 2A and 2B domains, but demonstrates
it to be a continuous a-helix [123].
Desmin is a highly insoluble protein and hence it can be
Desmin protein kept in solution as a monomer and purified only under
highly denaturing conditions as provided by buffers con-
Protein structure and filament assembly taining 8 M urea. For assembly, it is usually first re-natured
by dialysis into buffers of low salt such as 2 mM sodium
Human desmin is a 470-amino acid protein ([79, 153]; phosphate (pH 7.5). The assembly process starts actually
UniProtKB/Swiss-Prot database entry P17661) with a cal- during the course of re-naturation, and two molecules
culated molecular weight of 53.5 kDa. Like all IF proteins, dimerize by coiled-coil formation of the central a-helical
it is fibrous in nature, exhibiting a tripartite structure with a rod domains of two desmin monomers in parallel orienta-
central, mostly a-helical domain of conserved size, i.e., tion [77]. A so-called heptad repeat pattern, which is
*45 nm. This so-called ‘‘rod’’ is flanked by non-a-helical characteristic for a coiled-coil structure [26], drives the
amino-terminal (‘‘head’’) and carboxy-terminal (‘‘tail’’) supercoiling of the two helices, yielding the dimeric,
domains of highly varying amino acid number [73] elongated structure. Two of these coiled-coil dimers further
(Fig. 4a). The ‘‘rod’’ domain comprises two continuous associate in a half-staggered, anti-parallel fashion to a
a-helical segments, coil 1 and coil 2, which are connected tetramer of *60 nm length [77, 107] (Fig. 5a). These
by a ‘‘linker’’ (L12) of unknown structure. The current tetramers are able to spontaneously assemble into highly

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Table 1 Human desmin mutations, clinical phenotypes, myopathology, and related in vitro data
Row Domain Mutation Mutation type Mode of Phenotype Histology References
no. inheritance

123
1 Head Ser2lle Missense AD gM, cM, ri sva [167, 190]
2 Ser7Phe Missense (Fig. 2 of reference) AD n.a. n.a. [55, 56]
3 Ser12Phe Missense AD pM, dM, cM, ary sva, atf, intN, [83]
rvac
4 Ser13Phe Missense AD pM, dM, cM, ary sva, atf, intN, [21, 139, 167, 184,
rvac 185]
5 Arg16Cys Missense AR cM, ary atf, intN, rvac [4, 167]
6 Ser46Phe Missense AD n.a. sva [167]
7 Ser46Tyr Missense AD n.a. sva [167]
8 Coil 1A Glu108Lys Missense AD cM, ary n.a. [178]
9 Gln113fsX115 Frame shift SP gM, cM, ary sva, intN [83]
10 Glu114del Small in-frame deletion AD gM, cM, ary sva, intN, ppa [186]
11 Asn116Ser Missense SP (gM), cM, ary sva, atf [92]
12 Lys144X Frame shift AD gM, cM, ary, ri n.a. [190]
13 Coil 1B Arg173_Glu179del Small in-frame deletion AR gM, cM, ri, ary atf, intN, ppa
14 Ala213Val Missense, putative polymorphism AD, SP pM, dM, cM, ary Necrosis, ppa [57, 62, 95]
15 Asp214_Glu245del Splice site mutations leading to loss of exon 3: c.640-2A[T, c.640-1 G[A, AD, SP gM, pM, cM, 4par, sva, rvac, ppa [35, 42, 59, 64,
c.735G[C, c.735G[T, c.735 ? 1G[A, c.735 ? 3A[G ary, ri 135, 190]
16 Lys240del Small in-frame deletion, corrected from p.Lys239fsX242 (*) AD gM pM, ary sva, ppa [158, 159]
17 Glu245Asp Missense AD gM 4par, cM, ary, sva, atf, intN, [35, 66, 173, 189]
(ri) rvac
18 Coil 2 Leu274Arg Missense AD gM cM, ary sva, intN [83]
19 Leu274Pro Missense AD gM cM, ary sva, intN [83]
20 Ser298Leu Missense AD cM ary n.a. [178]
21 Asp312Asn Missense AD cM n.a. [178]
22 Arg335Pro Missense AD gM ary sva, intN [83]
23 Asp336Tyr Missense AD gM cM, ary n.a. [190]
24 Ala337Pro Missense AD gM pM, dM, cM, atf, intN, ppa [42, 58, 62, 199]
ary, ri
25 Leu338Arg Missense AD gM pM, dM, ri ppa [62, 190]
26 Asp339Tyr Missense SP dM ri n.a. [173]
27 Asn342Asp Missense AD, SP gM pM, dM, cM, atf, intN, ppa [41, 42, 133, 184,
ri, ary 190]
28 Leu345Pro Missense AD pM dM, cM, ary sva, atf, intN, [169, 190]
rvac
29 Arg350Pro Missense AD gM pM, dM, spM, sva, atf, intN [12, 173]
cM, ary
Acta Neuropathol (2013) 125:47–75
 Table 1 continued
Row Domain Mutation Mutation type Mode of Phenotype Histology References
no. inheritance

30 Arg350Trp Missense AD cM n.a. [178]

31 Arg355Pro Missense AD gM pM,dM,cM sva, atf, intN [47, 190]
32 Ala357Pro Missense AD gM pM, dM, spM, atf, ppa [39]
ri
33 Glu359_Ser361del Small in-frame deletion AD gM pM,dM atf, ppa [89]
34 Ala360Pro Missense, compound heterozygote (Asn393lle) AR gM pM, dM, cM, atf, intN, ppa [42, 58, 62]
ary, ri
Acta Neuropathol (2013) 125:47–75

35 Asn366del Small in-frame deletion AD gM pM, dM, cM, ppa [89, 129]
ary, ri
36 Ne367Phe Missense AD gM pM, dM, cM, sva, intN, rvac, [128]
ary, ri ppa
37 Leu370Pro Missense AD gM pM, dM, cM, sva, atf, intN, [5, 39]
ary, ri rvac, ppa
38 Leu377Pro Missense SP gM cM, ri n.a. [173]
39 Leu385Pro Missense SP gM cM, ary, ri sva [174]
40 Gln389Pro Missense SP pM dM, cM, ary sva, ppa [62]
41 Leu392Pro Missense AD gM pM, dM, cM, sva, intN, rvac, [128]
ary, ri ppa
42 Asn393lle Missense, compound heterozygote (Ala360Pro) AR gM cM, ary, ri atf, intN, ppa [42, 58, 62]
43 Asp399Tyr Missense AD pM dM, cM, ri, ary atf, ppa [62]
44 Glu401Lys Missense SP gM pM, dM, cM, atf, ppa, rvac [62]
ary, ri
45 Arg406Trp Missense AD, SP gM pM, dM, cM, atf, intN [4, 40, 42, 129,
ary, ri 136, 190]
46 Tail Glu413Lys Missense AD gM pM, dM, cM, sva, atf, intN, [10, 144]
ary ppa
47 Glu413Arg Missense AD gM cM, ary n.a. [190]
48 Arg415Trp Missense (Fig. 2 of reference) AD n.a n.a. [55, 56]
49 Pro419Ser Missense AD gM pM, dM,cM, sva, intN, rvac, [69, 128, 190]
ary ppa
50 Glu439Lys Missense AD gM cM, ary n.a. [190]
51 Thr442lle Missense AD, SP gM pM, dM, cM, atf, intN, rvac [10, 14, 175, 190]
ary
52 Thr445Ala Missense SP gM ri atf, intN, rvac [83]
53 Lys449Thr Missense AD, SP n.a n.a. [10, 14]
54 lle451Met Missense AD, SP gM pM, dM, cM, ri atf, intN, rvac, [14, 41, 42, 102,
ppa 118]
55 Thr453lle Missense AD, SP cM ary ppa [4]
55

123
 56

Table 1 continued
Row Domain Mutation Mutation type Mode of Phenotype Histology References
no. inheritance

123
56 Arg454Trp Missense AD, SP gM pM, dM, cM, atf, ppa [10, 133, 190]
ary, ri
57 Glu457Val Missense AD gM cM, ary sva, atf, intN [83]
58 Val459lle Missense AD cM ary n.a. [190]
59 Ser460lle Missense AD pM dM, cM, ary sva, atf, rvac [10, 14]
60 Val469Met Missense AD pM dM,cM n.a. [10, 14]
61 X471Tyr Missense/loss of stop codon AD pM dM, ary n.a. [190]
Row no. Immunostains Ultrastructure Assembly Assembly mix Tranfection Tranfection References
of Mut Mut/WT into IF negative into IF positive
cell cell

1 n.a. n.a. FNF, (Irw) FNF FNF (SW13), FNF FNF (HL-1) [167, 190]
(VimK0 MEF)
2 n.a. n.a. n.a. n.a. n.a. n.a. [55, 56]
3 des, abc, dys GFM n.a. n.a. Agg (SW13) Agg (C2C12) [83]
4 des Microgranular densities Agg FNF FNF/Agg (MCF7), SFF FNF/Agg (BHK21), [21, 139, 167, 184, 185]
(SW13), FNF/Agg Agg (HL-1)
(VimK0 MEF)
5 des Dense material Agg FNF FNF (SW13), FNF/Agg Agg(HL-1) [4, 167]
(VimK0 MEF)
6 n.a. n.a. FNF, (Irw) FNF SFF (SW13), FNF FNF (HL-1) [167]
(VimK0 MEF)
7 n.a. n.a. FNF, (Irw) FNF SFF (SW13), FNF FNF (HL-1) [167]
(VimK0 MEF)
8 n.a. n.a. n.a. n.a. FNF (SW13) FNF (hcasmc, nrcm) [178]
9 des, abc, dys, hyalin GFM n.a. n.a. Agg (SW13) Agg (C2C12) [83]
10 des GFM n.a. n.a. Agg (SW13), Agg(3T3) Agg (C2C12) [186]
11 des, myotilin GFM Agg FNF, Agg Agg (SW13) n.a. [92]
12 n.a. n.a. n.a. n.a. n.a. n.a. [190]
13 des GFM SFF SFF n.a. Agg (MCF7) [57, 121, 140]
14 n.a. n.a. Agg FNF (SW13), Agg FNF(C2C12) [57, 62, 95]
(BMGE ? H)
15 des GFM n.a. n.a. n.a. n.a. [35, 42, 59, 64, 135, 190]
16 des, syn, pic, ubi GFM n.a. n.a. Agg (SW13) Agg (BHK21) [158, 159]
17 des GFM n.a. n.a. n.a. n.a. [35, 66, 173, 189]
18 des, abc, dys GFM n.a. n.a. Agg (SW13) Agg (C2C12) [83]
19 des, abc, dys GFM n.a. n.a. Agg (SW13) Agg (C2C12) [83]
Acta Neuropathol (2013) 125:47–75
 Table 1 continued
Row no. Immunostains Ultrastructure Assembly Assembly mix Tranfection Tranfection References
of Mut Mut/WT into IF negative into IF positive
cell cell

20 n.a. n.a. n.a. n.a. Agg (SW13) Agg (hcasmc, nrcm) [178]
21 n.a. n.a. n.a. n.a. Agg (SW13) Agg (hcasmc, nrcm) [178]
22 des GFM n.a. n.a. Agg (SW13) Agg (C2C12) [83]
23 n.a. n.a. n.a. n.a. n.a. n.a. [190]
24 des GFM n.a. n.a. Agg (SW13) Agg (C2C12) [42, 58, 62, 199]
Acta Neuropathol (2013) 125:47–75

25 n.a. n.a. n.a. n.a. Agg (SW13) Agg (C2C12) [62, 190]
26 n.a. n.a. n.a. n.a. n.a. n.a. [173]
27 des GFM n.a. n.a. Agg (SW13) n.a. [41, 42, 133, 184, 190]
28 des, vim, nestin GFM n.a. n.a. Agg (SW13) Agg (HeLa) [169, 190]
29 des, abc, pic GFM ULF Agg Agg (MCF7, SW13, Agg (3T3-L1) [12, 173]
BMGE ? H)
30 n.a. n.a. n.a. n.a. Agg (SW13) Agg (hcasmc, nrcm) [178]
31 des, abc, dys, hyalin GFM n.a. n.a. n.a. n.a. [47, 190]
32 des GFM n.a. n.a. Agg (SW13) Agg (BHK21) [39]
33 abc GFM n.a. n.a. Agg(SW13) Agg (BHK21) [89]
34 des GFM n.a. n.a. Agg (SW13) FNF (C2C12) [42, 58, 62]
35 des GFM n.a. n.a. Agg (SW13) Agg (BHK21) [89, 129]
36 des, abc, fine, dys GFM n.a. n.a. n.a. n.a. [128]
37 des Disrupted myofibrils, GFM n.a. n.a. Agg (SW13) Agg (BHK21) [5, 39]
38 n.a. n.a. n.a. n.a. n.a. n.a. [173]
39 des GFM n.a. n.a. n.a. Agg/cell death (COS-7, [174]
CHO)
40 des GFM Agg Agg Agg (SW13) Agg (MCF7, C2.7) [62]
41 des, abc, fine, dys GFM n.a. n.a. n.a. n.a. [128]
42 des GFM n.a. n.a. Agg (SW13) Agg (C2C12) [42, 58, 62]
43 n.a. n.a. n.a. n.a. Agg (SW13) Agg (C2C12) [62]
44 n.a. n.a. n.a. n.a. Agg (SW13) Agg (C2C12) [62]
45 des GFM n.a. n.a. Agg (SW13) n.a, [4, 40, 42, 129, 136, 190]
46 des GFM ULF FNF, SFF Agg (SW13) Agg (C2C12) [10, 144]
47 n.a. n.a. n.a. n.a. n.a. n.a. [190]
48 n.a. n.a. n.a. n.a. n.a. n.a. [55, 56]
49 des, abc, fine, dys GFM n.a. n.a. n.a. n.a. [69, 128, 190]
50 n.a. n.a. n.a. n.a. n.a. n.a. [190]
51 des GFM FNF FNF FNF (SW13), FNF FNF (C2C12, HL-1) [10, 14, 175, 190]
(VimK0 MEF)
57

123
 58

Table 1 continued
Row no. Immunostains Ultrastructure Assembly Assembly mix Tranfection Tranfection References
of Mut Mut/WT into IF negative into IF positive

123
cell cell

52 des, abc, dys, hyalin GFM n.a. n.a. Agg (SW13) Agg (C2C12) [83]
53 n.a. FNF FNF FNF FNF (VimK0 MEF) FNF (HL-1) [10, 14]
54 des FNF FNF FNF FNF (SW13), FNF FNF (SW13, C2.7, [14, 41, 42, 102, 118]
(VimK0 MEF) MCF7, HL-1)
55 des Dense material n.a. n.a. n.a. n.a. [4]
56 des GFM, NSA SFF FNF Agg (SW13) FNF (C2C12) [10, 133, 190]
57 des, abc, dys, hyalin GFM n.a. n.a. Abnormal FNF (SW13) Aberrant FNF (C2C12) [83]
58 n.a. n.a. n.a. n.a. FNF/Agg (SW13) Agg (hcasmc, nrcm) [190]
59 des GFM FNF FNF Agg (SW13), FNF FNF (C2C12, HL-1) [10, 14]
(VimK0 MEF)
60 n.a. FNF FNF FNF FNF (SW13), FNF FNF (C2C12, HL-1) [10, 14]
(VimK0 MEF)
61 n.a. n.a. n.a. n.a. n.a. n.a. [190]

As of June 2012, 67 disease causing mutations of the DES gene have been published, which may give rise to the expression of 61 different mutant forms of the desmin protein. In addition, two
French patients with a virtually complete lack of desmin protein expression due to a homozygous 22-bp deletion in exon 6 (mutation not further specified, therefore not listed in Table 1) have
been described [31]. GenBank entry NM_001927.3 was used as desmin reference sequence; nucleotide numbering refers to the cDNA sequence with ?1 corresponding to the A of the ATG start
codon. Note of caution (*): The p.Lys239fsX242 insertion mutation, which subsequently had been corrected into p.Lys240del, erroneously has been cited as ‘‘ins245’’ [137] or ‘‘Glu245X’’ in
few later publications [27, 178]. Cell types in brackets in the columns ‘‘Transfection into’’ are described in the main text
Abbreviations in alphabetical order: 4par tetraparesis, abc aB-crystallin, AD autosomal dominant, Agg aggregates, AR autosomal recessive, ary cardiac arrhythmia, atf atrophic fibres, cM
cardiac myopathy, des desmin, dM distal myopathy, dys dystrophin, flnc filamin-C, FNF filament/network formation, GFM granulofilamentous material, gM generalized myopathy, intN
internalized nuclei, Irw irregular filament width, n.a. not available, NSA negative-stained assemblies, plc plectin, pM proximal myopathy, ppa pathological protein aggregates/inclusions/
deposits, ri respiratory insufficiency, rvac rimmed vacuoles, SFF short filament formation, SP sporadic, spM scapuloperoneal myopathy, sva size variability, syn synemin, ubi ubiquitin, ULF
unit length filaments/ULF-like blobs, vim vimentin
Acta Neuropathol (2013) 125:47–75
Acta Neuropathol (2013) 125:47–75 59

ordered long filaments upon increase of the ionic strength of 58 kDa. In addition to muscle, desmin expression has
to physiological values. The assembly process can be been described in a wide variety of normal and diseased
described to occur in three phases: (1) The lateral par- cells, for example, pericytes [24], hepatic stellate cells
allel assembly of tetramers yielding full-width, 60-nm- [124], myoid stromal cells of placenta [170], Sertoli cells
long filaments that have been termed unit-length fila- [148], decidual cells [67], injured glomerular podocytes
ments or ULFs [71, 77] (Fig. 5b). (2) The formation of [70], and mesotelioma cells [85].
extended intermediate filaments by serial longitudinal Desmin is one of the earliest markers of muscle devel-
annealing of ULFs and further longitudinal annealing of opment [27], and this is true for all vertebrates including
short filaments [71] (Fig. 5c1,c2,c3,d). (3) After a few amphibian and fish, pointing to an important evolutionary
minutes of assembly, filaments undergo a final matura- conservation [75, 153]. Its expression precedes all other
tion step characterized by a radial compaction process muscle-specific structural proteins and even—with the
[76, 79]. exception of myf-5—the expression of the myogenic
transcription factors myoD, myogenin, and mrf4 (myf-6)
Protein expression [99, 103, 112]. During early muscle development desmin
and vimentin are co-expressed. Vimentin is the most
Desmin is the most abundant IF protein in striated and abundant IF protein of immature myoblasts. Upon further
smooth muscle cells. Immunoblotting after one-dimen- differentiation into mature muscle cells, desmin is strongly
sional SDS-PAGE with desmin-specific antibodies shows a upregulated, while the expression of vimentin is com-
single band corresponding to an apparent molecular weight pletely ceased [43, 152].

Fig. 5 Schematic model of

cytoplasmic IF assembly. a Two
dimers associate in an anti-
parallel, half-staggered fashion
by overlap of the two coiled
coils via their coil1, i.e., coil 1A
and coil 1B (brown segments).
b Upon initiation of assembly
conditions the tetramers
associate laterally into a unit-
length filament (ULF). In
vimentin, a ULF counts eight
tetramers on the average [76].
c Individual ULFs may
longitudinally anneal with
another ULF (c1) or with a
filament consisting of two
annealed ULFs (c2); eventually,
two short filaments may
longitudinally anneal to a longer
filament (c3). d Upon extended
incubation, long filaments will
spontaneously reduce their
diameter by radial compaction
to form a mature IF [76]. The
figure is redrawn and modified
after [79]

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Post-translational modifications directly bind to genomic DNA and to exert a role in tran-
scription regulation and DNA organization [182]. Roles of
Post-translational modifications do play an important role desmin in the morphology and homeostasis of myonuclei,
in regulating the functions of intermediate filaments. mitochondria, and lysosomes are discussed in the respec-
In vitro translation of chicken skeletal and smooth muscle tive paragraphs on muscle pathology, desmin binding
desmin using a cell-free rabbit reticulocyte system resulted partners, and desmin mouse models. Biomechanical
in predominantly non-phosphorylated desmin, suggesting a aspects of desmin at the level of single IFs, myoblasts,
low amount of phosphorylated desmin under basal condi- myofibers, and whole muscle are summarized in the
tions [125]. On the other hand, desmin has been described respective paragraph on biomechanics.
as one of the major acceptors of 32P in differentiating
chicken myotubes. Two-dimensional tryptic analysis of Molecular interaction partners
desmin revealed multiple sites of phosphorylation [52].
Another study showed that desmin is a substrate of the p21- Desmin exerts its multiple functions through direct and
activated kinase (PAK) mainly leading to phosphorylation indirect binding to various other cellular molecules. In the
of serine residues within the desmin ‘‘head’’ domain. PAK- past 4 decades of desmin research, a growing number of
mediated phosphorylation of desmin strongly inhibited its desmin binding partners has been described (see also a
filament-forming ability [127]. Assembly is also inhibited previous review on desmin interactions [38]). The follow-
by ADP ribosylation of desmin via an arginine-specific ing description of desmin interactions is confined to
mono-ADP-ribosyltransferase of muscle, which primarily binding partners that are present in muscle cells, i.e., IF
targets arginine 48 and to a lesser extent arginine 68 within proteins, IF-associated proteins, sarcomeric proteins,
the desmin ‘‘head’’ domain [201]. A subsequent study membrane-associated proteins, small heat shock proteins,
provided evidence that ADP-ribosylated desmin neither apoptosis-related proteins, and nucleic acids.
co-assembles with nor affects the filament formation of
non-modified desmin. In contrast, the ADP-ribosylation Interactions with other IF proteins
of pre-formed desmin IFs resulted in their disassembly.
Furthermore, this process is dependent on the phosphory- During muscle development and maintenance, desmin has
lation of additional amino acid residues [198]. been reported to interact with five IF proteins, i.e.,
vimentin, nestin, synemin (also known as desmuslin), and
Subcellular localization and functions syncoilin, which all are expressed in a spatiotemporal
pattern. In addition, the nuclear B-type lamins have been
Desmin immunostaining of cross-sectioned striated muscle claimed to be a direct binding partner of desmin [54, 111].
revealed sarcoplasmic and subsarcolemmal localizations. With the cytoplasmic IF-proteins the situation is much
In longitudinal sections, desmin immunostains revealed a clearer: Desmin and vimentin are closely related class III
cross-striated pattern [162]. In addition, desmin is enriched IF proteins, whereas nestin, synemin, and syncoilin are
at the level of myotendinous and neuromuscular junctions more distantly related class IV IF proteins. Desmin,
of skeletal muscle as well as of intercalated discs in cardiac vimentin, and nestin are co-expressed and colocalized in
muscle [30, 180]. Immunogold electron microscopy dem- myoblasts. Vimentin and nestin have each been demon-
onstrated the presence of desmin at costameres, strated to assemble into ‘‘heteropolymeric’’ IFs with
filamentous structures spanning between myofibrils and the desmin [74, 79, 172]. While vimentin expression is
overlaying sacolemma, filamentous inter-Z-disc structures downregulated, desmin and nestin are further expressed in
of neighboring myofibrils and mitochondria, and at the later stages of myogenesis [168]. In contrast to desmin,
desmosomal plaque of intercalated discs, where desmin IFs nestin is primarily retained at myotendinous and neuro-
bind to desmoplakin, a member of the plakin family of muscular junctions in mature skeletal muscle [28].
crossbridging proteins [90, 111, 146, 162]. Moreover, synemin was found to co-purify and colocalize
This three-dimensional filamentous extra-sarcomeric with desmin and vimentin [63]. However, synemin seems
desmin cytoskeleton interlinks neighboring myofibrils not to participate in the formation of mixed filaments, but
(Fig. 6) and connects the myofibrillar apparatus with binds to pre-formed desmin or vimentin IFs [18, 81, 150].
myonuclei, other cell organelles, and the extracellular In mature skeletal muscle, synemin is localized at the
matrix via the subsarcolemmal cytoskeleton [27, 160]. periphery of Z-discs and at the sarcolemma ([119], and
Beyond a sole mechanical integration, this complex inter- own observations). Another IF protein that directly inter-
action is thought to be the basis for a mechano-chemical acts and colocalizes with desmin in mature skeletal muscle
signaling between various compartments. IFs in general is syncoilin, which is localized at neuromuscular junctions,
and desmin in particular have also been hypothesized to the sarcolemma, and Z-discs. Similar to synemin, syncoilin

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Acta Neuropathol (2013) 125:47–75 61

Fig. 6 Schematic of the desmin IF network in relation to the pathological protein aggregation, mitochondrial abnormalities, and
myofibrillar apparatus. In desminopathies, mutant desmin leads to signs of myofibrillar degeneration
structural and functional changes of the extrasarcomeric cytoskeleton,

binds to IFs but does not participate in the formation of the two plectin isoforms 1d and 1f link desmin IFs to
mixed filaments and therefore should be called an IF- Z-discs and costameres, respectively, whereas isoform 1b
associated protein. Syncoilin has been postulated to play a links desmin to mitochondria [93]. Plectin has been
role in the cytoskeletal anchorage of the desmin IF [142]. reported to directly bind to the coiled-coil rod domain of
desmin via its fifth plakin repeat domain and part of the
Interactions with IF-associated proteins following linker domain [45]. During myodifferentiation
desmin has been shown to co-purify and colocalize with
Desmin directly interacts with multiple IF-associated pro- paranemin—the chicken ortholog of mammalian nestin
teins. The proper structural and functional organization of [147]—at the level of Z-discs in myotubes. In contrast to
the desmin IF system highly depends on the interaction of plectin but similar to nestin, paranemin is downregulated
desmin with several plectin isoforms. In skeletal muscle, upon differentiation and absent in mature muscle cells [25].

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Paranemin has been described to associate with desmin submembranous organization of the motor end plate
IFs—but not to form heteropolymers—leading to the for- [117].
mation of an extended desmin IF network [163]. A further
direct desmin binding protein is myospryn (or cardio- Interactions with small heat shock proteins, apoptosis-
myopathy-associated protein 5), a component of the related proteins, and nucleic acids
biogenesis of lysosome-related organelles complex 1
(BLOC-1). This interaction involves the desmin ‘‘head’’ The two small heat shock proteins HspB1 (synonyms:
domain and a 24-amino acid motif at the end of the SPRY Hsp25, Hsp27) and HspB5 (synonym: aB-crystallin)
domain of myospryn. Both proteins colocalize in close directly bind to desmin [19, 91]. The interaction of HspB1
relation to the nucleus and the endoplasmic reticulum in with desmin depends of the phosphorylation of HspB1 at
neonatal cardiomyocytes as well as at intercalated discs, serine residue 15 [91]. Furthermore, desmin has been
costameres, and lysosomes in adult cardiac muscle. It has identified as a substrate of caspase-6 and calpains. During
been postulated that the desmin–myospryn interaction the process of apoptosis, caspase-6 cleaves human desmin
plays a role in lysosome biogenesis and positioning [96]. at the conserved asparagine 264 (corresponds to mouse
Moreover, desmin has been shown to interact with myo- desmin Asp263) located in the L12 linker (Fig. 4). The
tubularin, a protein mutated in X-linked centronuclear N-terminal desmin cleavage product has been considered
myopathy (XLCNM or myotubular myopathy). XLCNM- to play a role in the execution of apoptosis via a dominant-
causing mutations of myotubularin were found to interfere negative effect on the desmin IF network integrity [32].
with the desmin–myotubularin interaction resulting in an Desmin also is a specific target of the proteolytic calpain
abnormal desmin IF network in skeletal muscle. Further- (Ca2?-activated cysteine proteinase) system [60]. The
more, downregulation as well as expression of mutant limited proteolysis of desmin by calpains results in desmin
myotubularin both induced morphological and functional ‘‘head,’’ ‘‘rod,’’ and ‘‘tail’’ domain cleavage products,
defects of mitochondria [82]. In myometrial cells, desmin which are no longer capable to participate in desmin IF
has been found to directly interact with surfactant protein A formation, but instead heavily interfere with the proper
(SP-A), a member of the collectin family of proteins. This assembly process [15, 17, 122]. The calpain system has
interaction has been reported to inhibit the polymerization also been attributed to exert a role in the spatiotemporal
of desmin IFs [51]. regulation of desmin protein levels during myotube for-
mation [44]. Like other IF proteins, the head domain of
Interactions with sarcomeric and membrane-associated desmin has been demonstrated to bind to single-stranded
proteins RNA and DNA molecules in vitro [188, 192]. This prop-
erty reflects the high proportion of basic residues (12
Desmin has been reported to directly interact with com- arginines) and the absence of negatively charged residues
ponents of the myofibrillar apparatus. The M-line protein in the non-a-helical ‘‘head’’ domain. The in vitro interac-
myomesin-1 (synonym: skelemin) was first described as a tion of desmin and DNA is preferentially targeted to
desmin binding partner in striated muscle [143]. In addi- exposed single-stranded sites of repetitive and mobile DNA
tion, the coiled-coil rod domain of desmin interacts with sequence motifs and seems to induce changes of the DNA
the Z-disc section of nebulin [8]. Smooth muscle basic configuration [181].
calponin, a major actin-, tropomyosin-, and calmodulin-
binding protein, has been identified as a third sarcomeric
desmin binding partner, which also interacts with the Pathophysiology
desmin rod domain [50].
The desmin IF network of muscle cells is anchored to Subcellular localization and expression of wild-type
the subsarcolemmal cytoskeleton of costameres. In this and mutant desmin
respect, desmin has been reported to bind to red blood
cell spectrin and it has been postulated that non-red blood Analysis of single skeletal muscle fibers from a patient
cell spectrins also may mediate the association of the with the heterozygous p.Arg350Pro desmin mutation
desmin IF network with the plasma membrane [101]. A showed the presence of pathological desmin-positive pro-
further link between the desmin IF network and the tein aggregates in conjunction with the normal cross-
subsarcolemmal cytoskeleton is provided by the direct striated desmin staining pattern [158, 159] (Fig. 7). This
interaction of an N-terminal region of the desmin head finding raises the question whether mutant desmin forms
domain with ankyrin [54]. Moreover, desmin was found mixed desmin IFs or mixed aggregates with wild-type
to directly or indirectly interact with the nicotinic ace- desmin or if the mutant protein segregates from the wild-
tylcholine receptor, where it has a postulated role in the type protein. This issue cannot be solved using

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Acta Neuropathol (2013) 125:47–75 63

wild-type band. However, no desmin mutation analysis was

reported [3]. In another study on a desminopathy due to a
heterozygous c.735G[C mutation, desmin immunoblotting
revealed the presence of two bands at the positions
of 53 kDa and 50 kDa. However, RT-PCR analysis in
this particular family identified three distinct desmin
mRNA species coding for wild-type and p.Glu245Asp
desmin, which both are visible at 53 kDa, as well as
p.Asp214_Glu245del corresponding to the truncated
50-kDa protein. Here, the amount of the truncated desmin
protein varied between 5 and 43 % [35]. Two-dimensional
desmin gel electrophoresis in desminopathies revealed
non-uniform results. In a desminopathy due to the hetero-
zygous p.Lys240del mutation, an aberrant and more acidic
spectrum of desmin spots was visible [158, 159], whereas
the p.Asp214_Glu245del desmin mutant species presented
with a more alkaline pI [35].

Aberrant modifications of desmin

Desmin has been found to be oxidated and nitrated in

muscle fibers containing pathological protein aggregates.
These modifications may have a direct cytotoxic effect and
may impair the degradation via the ubiquitin-proteasom
system [87]. Beyond specific desmin modifications, skel-
etal muscle samples from desminopathies exhibited
increased levels of glycoxidated, lipoxidated, and nitrated
proteins [88].

Dysfunctions in protein quality control

A study demonstrated an increased immunoreactivity of

the 20S proteasome core as well as its 19S and 11S
(synonyms: PA28alpha/beta, PSME1/PSME2) regulators
co-localizing with pathological protein aggregates in
Fig. 7 Indirect immunofluorescence labeling of desmin and syncoilin
desminopathies. Further components of the immunopro-
in an isolated muscle fiber from a desminopathy. Note the presence of teasome have also been reported to colocalize with the
multiple pathological protein aggregates in addition to the normal protein aggregates [46]. Another study demonstrated an
cross-striated staining pattern of these two proteins enrichment and co-localization of the mutant ubiquitin
UBB?1 as well as the autophagy-related p62 with desmin-
commercially available desmin antibodies as they do not positive protein aggregates in desminopathies [131]. Des-
distinguish between the wild-type and the point-mutated min-positive protein aggregates in desminopathies also
desmin protein species. show a positive immunoreactivity with antibodies directed
Studies on desmin protein expression in desminopathies against HspB1 (synonyms: Hsp25, Hsp27) and HspB5
due to deletion or frame-shift mutations would allow at (synonym: aB-crystallin) [160]. With regard to HspB1,
least the determination of the expression level of the two-dimensional gel electrophoresis demonstrated a shift
mutant desmin species. However, only two studies reported of the main HspB1 spot to a more alkaline pI [36]. Further
such data yet. In one study immunoblotting revealed two relationships between the expression of mutant desmin and
desmin bands in cardiac and skeletal muscle with the lower the ubiquitin–proteasome system, autophagy, and heat
band corresponding to a truncated desmin protein species shock proteins are provided in the respective paragraphs on
showing an intensity of approximately 30 % of the upper desmin mouse models.

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Mitochondrial pathology desmin dots aligning with the red vimentin IFs). In the
collapsed area, the green and the red signals superimpose
SDH and COX stains of skeletal muscle biopsy specimens to yield a yellow signal; however, the signals differ
from desminopathy patients often show areas with either entirely in shape, dots versus fibers, indicating that they
increased or decreased enzyme activities (Fig. 1c). With are not contained within the same structure but are only
regard to a putative mitochondrial pathology, an analysis of located close to each other and thereby generate a yellow
the mitochondrial function in isolated saponin-permeab- signal.
lized skeletal muscle fibres from a desminopathy patient
(heterozygous p.Lys240del desmin mutation) revealed an In vitro filament assembly
in vivo inhibition of complex I activity [158, 159].
The first disease mutant desmin to be analyzed at the
Cytoskeletal organization in vitro level for its assembly properties was the rather
drastic p.Arg173_Glu179del desmin ‘‘rod’’ mutation,
Desmin transfection studies have been performed in a which misses seven amino acids in a row in coil 1B. In
variety of muscle and non-muscle cell types: BHK21 both cell culture after cDNA-transfection and after forced
(ATCC CCL-10) hamster kidney fibroblasts express des- assembly of recombinant proteins, only non-IF structures
min and vimentin intermediate filaments [80]. HL-1 were obtained [121]. Later on, several other desmin disease
cardiac [34], C2C12 (ATCC CRL-1772), and inducible mutants were studied, and their ability to form IF networks
C2.7 [141] skeletal muscle-derived mouse myoblasts, in vivo was analyzed by cellular cDNA transfection [11].
human coronary artery smooth muscle (hcasmc), and In order to reveal how desmin mutations influence basic
neonatal rat cardiac ventricular myocytes (nrcm) [178] as filament assembly properties, a consecutive study investi-
well as C3H/10T1/2 (ATCC CCL-226) mouse fibroblasts gated their assembly properties at the protein level [12].
ectopically expressing Myf5 or MyoD all contain desmin Four major classes of pathological effects were observed
and vimentin IFs. 3T3 (ATCC CRL-1658) mouse fibro- (Fig. 9): (1) after 10 s of assembly, filaments form by
blasts contain vimentin. Vimentin-free mouse embryonic lateral association of tetramers and subsequent longitudinal
fibroblasts (MEFs) isolated from vimentin knockout mice annealing of ULFs (see also Fig. 5); however, upon further
and spontaneously immortalized do not express cytoplas- incubation these IF-like filaments show an abnormal lateral
mic IF proteins [37]. Moreover, both MCF7 (ATCC HTB- annealing leading to the formation of large ‘‘sheets’’
22) human epithelial cells and bovine mammary gland (Fig. 9, p.Asn342Asp); (2) a second class forms IFs similar
epithelium cells grown in the presence of hormones to those generated from desmin WT, although the filaments
BMGE?H [154] are vimentin-free and express only ker- are less regular (Fig. 9, p.Ala360Pro); (3) other mutants
atin IF proteins. SW13 (ATCC CCL-105) human epithelial exhibit extended filaments at 10 s of assembly, but there-
cells do not express any IF protein. after immediately decay into ball-like aggregates [13]
The overall data derived from studies using these cell (Fig. 9, p.Leu370Pro); (4) filament assembly starts with
types indicated that the majority of desmin mutants are apparently normal ULFs; however, they fail to longitudi-
incapable of forming a de novo desmin IF network, but nally anneal as observed with wild-type desmin and instead
instead form non-IF structures and desmin-positive protein stay at the ULF-state or loosely associate longitudinally
aggregates. In addition, most of them induce the collapse of such that the sub-filament structure remains visible (Fig. 9,
a pre-existing IF network such as in 3T3 cells, although p.Arg406Trp). Notably, all desmin disease mutants that
several mutant desmin proteins integrate well, just like the were not able to form stable filaments on their own in vitro
wild-type protein, into the vimentin network [9, 11, 16, also did not form IFs after transfection into IF-free cells.
167]. As an example, we depict here the transfection of the Instead, they did segregate from the endogenous IF system
p.Arg406Trp desmin rod mutant into various cell types. In when transfected into vimentin- or desmin-containing cells
the vimentin-free SW13 and BMGE?H cells, it forms dot- [13]. While the finding that truncated desmin mutants did
like and short rod-like structures (Fig. 8a, b); in addition, in not properly assemble is not that unexpected, the observed
3T3 cells it completely segregates from the endogenous high pathogenicity of missense mutations suggests that
vimentin filaments and causes the reorganization of desmin filament assembly is a delicate process that can be
vimentin IFs around the nucleus (Fig. 8c). Similarly, the easily distorted.
p.Leu345Pro desmin mutant completely avoids integrating
into the vimentin system (Fig. 8d–f); however, some Biomechanics: from filaments to cells and muscle tissue
affinity for vimentin is observed in extended vimentin IFs
below the cell nucleus and outside of the area of the col- A characteristic biophysical property of IFs is their elas-
lapsed vimentin IFs (Fig. 8f, arrowheads denote green ticity. In response to mechanical stretch, desmin filaments

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Fig. 8 Ectopic expression of mutant desmin in cultured cells. The expression. In contrast to wild-type desmin, the mutant does not
desmin mutant p.Arg406Trp was transfected into (a) IF-free human integrate into vimentin filaments [11]. Similarly, the desmin mutant
SW13 cells; b vimentin- and desmin-free bovine mammary gland p.Leu345Pro (proline is often called a ‘‘helix breaker’’) segregates
cells (BMGE?H) containing cytokeratins; and c into mouse fibroblast from the endogenous vimentin system when transfected into 3T3
3T3 cells. Detection was by specific primary and secondary antibod- cells: d desmin antibody staining; e vimentin antibody staining;
ies: desmin stain in green, vimentin in red. Note that the p.Arg406Trp f merged image highlighting green dot-like desmin structures on red
desmin mutant does not form filaments on its own, and also in the vimentin filaments (arrowheads). Also in areas where both proteins
vimentin-containing cell the desmin mutant protein stays particulate. are present, they clearly are in distinct structures. Images are taken
Note furthermore that the vimentin system is re-organized (‘‘col- from [11]
lapsed’’) around the nucleus as a consequence of the mutant desmin

have been shown to extend in length in conjunction with a that of wild-type desmin, while others displayed changes in
thinning of their diameter. Experiments demonstrated that their tensile properties with reduced strain stiffening. Such
upon a 3.4-fold extension, desmin filaments reduced their an increase in the resistance of desmin filaments to
diameter from 12.6 to 3.5 nm [98]. Moreover, the phe- an external pulling force may inflict changes in the
nomenon that IFs become more viscoelastic when exposed adaptability of muscle cells to mechanosensing and
to an external mechanical force is referred to as ‘‘strain mechanotransduction [14, 97]. Analysis of primary cul-
stiffening’’ [86, 155]. In striated muscle, the elasticity of tured myoblasts derived from a patient with a heterozygous
desmin filaments has been attributed to play a cell-pro- p.Arg350Pro desmin mutation revealed an aberrant
tective role against mechanical stress. Thus, desmin response to mechanical stress. These cells displayed
filaments may dissipate mechanical energy during muscle increased cell stiffness and a higher rate of cell death and
contraction. substrate detachment [22]. A number of biomechanical
In this context, mutant desmin may exert a pathogenic studies on mice lacking desmin have been reported. One
effect on the viscoelastic properties of the desmin filament study provided evidence that the lack of desmin is asso-
system, which consecutively may lead to progressive ciated with a reduction of the overall passive elasticity of
muscle fiber damage and muscle weakness. The visco- intact isolated soleus muscle [2]. Another study focusing
elastic properties of several disease-associated mutant on the diaphragm reported a reduced stiffness and visco-
desmin protein species have been analyzed. Here, the focus elasticity of this muscle together with an increased tetanic
was on desmin mutants that are able to form apparently force production [23]. A further study showed a reduced
normal filament networks in vitro and in vivo. Some of passive tensile strength after eccentric contraction associ-
these mutants showed nanomechanical properties similar to ated with disrupted Z-discs in individual myofibrils.

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b Fig. 9 In vitro filament assembly of wild-type desmin compared to

various mutants. Assembly was initiated at time point zero by
increase of the ionic strength of the incubation buffer and stopped at
10 s and 10 min, respectively, by addition of filament buffer
containing 0.2 % glutaraldehyde. The wild-type desmin (desmin
WT) and the mutants, indicated within the respective panels, were
analyzed after being negatively stained with uranyl acetate by
transmission electron microscopy. Images are taken from [12, 13]

desmin in excitation–contraction coupling [149]. This

assumption was further underlined by an additional study
reporting a defective excitation–contraction coupling in
intact extensor digitorum longus and soleus muscles of
desmin knockout mice. Here, the increased fatigue in
extensor digitorum longus muscle was assessed by con-
tinuous high frequency field stimulation and could be
overcome by the addition of caffeine. This combination of
results argues against a defect in the sarcoplasmic reticu-
lum calcium storage capacity [197]. However, this
interpretation was challenged by yet another study, which
used a more physiological high frequency stimulation
protocol with titanic trains. In this setting, a reduced fatigue
in intact soleus muscle without any change in the calcium
sensitivity of the contractile apparatus was observed [7].
Finally, a study described that the absence of desmin
resulted in an increased number of branched myofibers in
the flexor digitorum brevis muscle. This work reported
neither differences in the resting sarcoplasmic calcium
concentration nor in the sarcoplasmic calcium release
amplitude in desmin knockout myofibers [61].

Animal models

Desmin knockout models

Desko #1
and Desko #2

Desmin knockout mouse models from two independent

research groups were published in 1996 (Desko #1 [104] and
Desko #2 [116]). Desmin knockout mice were viable and
fertile and showed no overt defects in muscle development.
However, they developed clinical and morphological signs
of a progressive myopathy and cardiomyopathy [68, 104,
116]. The skeletal muscle pathology, most prominent in
weight-bearing muscles, was characterized by disorganized
and nonaligned fibers, Z-disc streaming, and subsarco-
lemmal accumulation of mitochondria. In addition,
myofibrillogenesis in regenerating muscles was reported to
be disturbed [104, 105, 116]. An in situ analysis of mito-
chondrial function revealed a reduced maximal rate of
In addition, the maximal isometric force production in the ADP-stimulated oxygen consumption [114]. Furthermore,
extensor digitorum longus muscle was reported to be an abnormal folding of the postsynaptic apparatus of the
decreased, which points to a possible involvement of neuromuscular junction was noted [1]. The lack of desmin

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led to changes in the subcellular distribution of synemin Desko #2

/Destg p.Asp263Glu
/TNFtg overexpression

and nestin (synonym: paranemin), but not of plectin [29].

Heart function of desmin knockout mice was investi- In the context of a mouse model for tumor necrosis factor
gated by a cardiac MRI study. This demonstrated alpha-induced cardiomyopathy, it was found that increased
significantly reduced left and right ventricular ejection expression of TNF-alpha leads to degradation and changes
fractions and cardiac output, an increased left ventricular in the subcellular distribution of desmin and to pathological
mass, and segmental wall thinning and akinesia [171]. aggregate formation. The latter process was attenuated in
In vivo electrophysiological studies revealed reduced atrial TNF-alpha overexpressing mice that additionally expressed
but prolonged ventricular refractory periods, ventricular p.Asp263Glu mutant desmin instead of the wild-type
conduction slowing, enhanced inducibility of atrial fibril- endogenous protein in the heart. This effect has been
lation, and a reduced susceptibility to ventricular attributed to a resistance of the mutant desmin to caspase-6
arrhythmias [157]. Histopathological analyses of cardiac cleavage [134].
tissue showed areas of hemorrhage, fibrosis, ischemia, and
calcification [104, 116]. Isolated cardiomyocytes showed Desmin transgenic mouse models
an increased cell volume [115]. In addition, changes in the
morphology of intercalated discs, disruptions of the sar- Destg truncated/chimeric desmin

colemma, as well as an abnormal shape and distribution of

mitochondria were observed [179]. The mitochondrial In 1996 the first transgenic desmin mouse was published
pathology in cardiac tissue was further characterized by an [145]. In this model a hamster desmin–vimentin chimeric
aberrant conventional kinesin (synonym: kinesin-1) distri- protein (last 129 aa of desmin replaced by last 13 aa of
bution, a lower amount of cytochrome c, and a re- vimentin) was expressed under control of the hamster
localization of Bcl-2 [109]. Furthermore, ketone body and desmin promoter. The expression of this truncated desmin
acetate metabolism, NADH shuttle proteins, amino-acid (approximately 10 % mutant compared to wild-type des-
metabolism, and respiratory enzymes were affected [49]. min) had a dominant-negative effect on the desmin IF
network. Desmin immunostains of skeletal and cardiac
Desko #2
/Bcl-2tg overexpression
muscle tissue revealed an aberrant desmin distribution
characterized by a loss of the cross-striated pattern.
The issue of cardiac pathology was further addressed by Ultrastructural analysis showed intermyofibrillar deposits
crossbreeding desmin knockout mice with transgenic mice of fibrillar and membranous electron-dense material and
overexpressing apoptosis regulator Bcl-2 [196]. These fragmented sarcomeres as well as abnormalities of the
double-mutant mice showed a reduced occurrence of T-tubule system.
fibrotic lesions in the myocardium, prevention of cardiac
hypertrophy, restoration of cardiomyocyte ultrastructure, Destg p.Arg173_Glu179del

and significant improvement of cardiac function. In addi-

tion, an improved calcium handling of mitochondria was A second transgenic desmin mouse model expressing a
observed. Hence, it was concluded that the mitochondrial desmin mutant with a small in-frame deletion of seven
abnormalities, which are regarded as the primary cause of amino acids was reported in 2001 [194] recapitulating the
the cardiomyopathy in desmin knockout mice, can be human mutation reported by [121]. A three-fold overex-
ameliorated by the overexpression of Bcl-2. pression of the p.Arg173_Glu179del desmin compared to
the endogenous wild-type desmin led to a dominant neg-
Desko #2
/Destg p.Ile451Met
ative effect with a disruption of the extra-sarcomeric
cytoskeleton and presence of desmin-positive granular fil-
In an additional study the desmin knockout strain was amentous protein aggregates in cardiac tissue. These
crossbred with another desmin mouse model with trans- animals further showed a compromised ability of the heart
genic expression of the p.Ile451Met mutant [113]. Note to respond to b-agonist stimulation. Control animals with a
that only mice homozygous for the desmin knockout and three-fold overexpression of wild-type desmin showed no
with presence of the p.Ile451Met desmin transgene were overt clinical or morphological effect. Skeletal muscle
analyzed. In this setting, the p.Ile451Met desmin showed tissue was not addressed in this study.
an aberrant subcellular distribution, was expressed at lower Electrophysiological investigations of this mouse model
levels (compared to wild-type desmin in wild-type control showed increased P-wave duration and slowing of ven-
mice), and was found to lack the N-terminal 20–30 amino tricular conduction [53]. Although no changes in the
acids. The latter finding has been attributed to a specific expression level of connexin-43, desmoplakin, plakoglo-
cleavage of the mutant desmin in cardiomyocytes. bin, and N-cadherin were observed, immunostains showed

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significantly reduced signal intensities of these junctional protein aggregates were detected, this animal presented
proteins. At the ultrastructural level, intercalated discs were evidence for a mitochondrial pathology characterized by
found to be highly convoluted and to contain fewer gap swelling and vacuolization as well as increased calcium
junctions and desmosomes. levels [94].

Destg p.Arg173_Glu179del
/Cryabtg p.ArgR120Gly

Conclusion and outlook

Cardiac pathology of the p.Arg173_Glu179del desmin
mouse was also analyzed after crossbreeding with trans- The last 2 decades have led to a number of important
genic mice overexpressing the p.ArgR120Gly mutant small insights into the molecular pathogenesis of desminopathies,
heat shock protein aB-crystallin [193]. This aB-crystallin but the precise and sequential molecular mechanisms
mutant had previously been shown to cause a cardiomy- leading from mutant desmin to consecutive pathological
opathy characterized by desmin-positive protein aggregates protein aggregation and progressive muscle damage still
in heterozygous humans and transgenic mice [187, 195]. remain to be elucidated. Though many desmin mutants
The double-mutant mice presented with an accentuated obviously compromise the desmin filament formation, the
cardiac pathology and died of congestive heart failure in progressive human muscle pathology cannot solely be
the first 2 months of life. Further analyses revealed attributed to such a simple mechanistic explanation. If
increased levels of desmin proteins and an increased desmin mutants have such a toxic effect on the desmin
abundance of pathological aggregates compared to filament system, why does it take decades of life until
p.Arg173_Glu179del desmin mice. clinical symptoms of muscle weakness become apparent?
Our review of the currently available data on desmin and
Destg p.Arg173_Glu179del
/GFPdgntg desminopathies enforces a complex and multilevel concept
of disease development in which mutant desmin addition-
The p.Arg173_Glu179del desmin mouse was further ally interferes with the binding to desmin interaction
crossbred with a transgenic mouse model expressing the partners, signaling cascades, protein quality control sys-
GFPdgn ubiquitin–proteasome system reporter substrate tems, and the function of cell organelles. Further work is
(GFP fused to an ubiquitination signal sequence) [100]. needed to evaluate, broaden, and integrate these different
This study provided evidence that the p.Arg173_Glu179del aspects. Respective future studies shall provide essential
mutant desmin impairs the proteolytic function of the novel insights into the atomic structure of the desmin tet-
ubiquitin-proteasome system by an impaired entry of ramer and its assembly reactions, the biomechanics of
ubiquitinated proteins into the 20S proteasome [110]. desmin-mutant cells and tissues, the expression and sub-
cellular localization of mutant desmin, the composition
Destg p.Arg173_Glu179del
/GFP-LC3tg of pathological protein aggregates, the characterization of
aberrant post-translational modifications and interactions of
Moreover, the p.Arg173_Glu179del desmin mouse had desmin with other proteins and nucleic acids, epigenetic
been crossed with a autophagy reporter mouse model factors, and dysfunction of various cell organelles. For
expressing a GFP-LC3 fusion protein [120]. Here, studies of early disease stages, the generation and charac-
expression of the desmin deletion mutant led to an terization of physiological cell and mouse models, i.e., with
increased autophagic flux associated with an increased a knockin of a desmin mutation into the murine desmin
expression of p62 [200]. gene, are necessary.
To date, no specific treatment is available for desmin-
Destg p.Leu345Pro
opathies and even basic clinical questions—e.g., is physical
exercise beneficial or harmful for the course of the dis-
The only transgenic mouse model expressing a desmin ease?—cannot finally be answered on the basis of the
missense mutation in addition to the endogenous protein currently available literature. A regular neurological, car-
was reported in 2008. The animal model with low diological, and pulmonological diagnostic workup is
expression (approximately 10 % of total desmin) of the certainly mandatory for all desminopathy patients. Future
HA-tagged p.Leu345Pro desmin mutant was reported to studies on desminopathy-related cell and animal models
show a reduced contractile function and recovery from will provide answers with respect to potential therapies: Do
fatigue in soleus muscle. Moreover, cardiac alterations anti-aggregation drugs such as small heat shock protein
consisting of a hypertrophic left ventricular posterior wall inducers and autophagy and proteasome modulators have a
and decreased left ventricular chamber dimension were cell-protective effect that ameliorates or even cures the
described. Though no MFM typical desmin-positive progressive muscle pathology? Or should we further

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explore muscle-specific gene transfer approaches, for of a novel heterozygous R350P desmin mutation on the
example, siRNA-based silencing of the mutant desmin assembly of desmin intermediate filaments in vivo and in vitro.
Hum Mol Genet 14:1251–1260
allele, overexpression of the wild-type desmin, or expres- 10. Bär H, Goudeau B, Walde S, Casteras-Simon M, Mücke N,
sion of other protective proteins such as heat shock proteins Shatunov A, Goldberg YP, Clarke C, Holton JL, Eymard B,
and Bcl-2? Katus HA, Fardeau M, Goldfarb L, Vicart P, Herrmann H
(2007) Conspicuous involvement of desmin tail mutations in
Acknowledgments This work is supported by grants of the Deut- diverse cardiac and skeletal myopathies. Hum Mutat 28:374–
sche Forschungsgemeinschaft (DFG) awarded to C.S.C, H.H., and 386
R.S. (FOR1228: CL 381/7-1; HE 1853/9-1, 9-2; SCHR 562/13-1). For 11. Bär H, Kostareva A, Sjoberg G, Sejersen T, Katus HA, Herr-
this work C.S.C. and R.S. are also supported by the Deutsche mann H (2006) Forced expression of desmin and desmin
Gesellschaft für Muskelkranke e.V. (DGM). Furthermore, R.S. is mutants in cultured cells: impact of myopathic missense muta-
supported by the Johannes & Frieda Marohn Stiftung. S.V.S. was tions in the central coiled-coil domain on network formation.
supported by the Katholieke Universiteit Leuven Research Supple- Exp Cell Res 312:1554–1565
ment (OT) grant 07/071 and by the Research Foundation Flanders 12. Bär H, Mücke N, Kostareva A, Sjoberg G, Aebi U, Herrmann H
(FWO) grant G.0709.12. We are grateful to Prof. Oliver Friedrich (2005) Severe muscle disease-causing desmin mutations inter-
(University of Erlangen-Nuremberg) for his input on biomechanical fere with in vitro filament assembly at distinct stages. Proc Natl
aspects, to Mr. cand. med. Gerrit Haaker (University Hospital Er- Acad Sci USA 102:15099–15104
langen) for assistance with data acquisition for Table 1, and Mr. 13. Bär H, Mücke N, Ringler P, Müller SA, Kreplak L, Katus HA,
Matthias Bähre for his assistance in preparation of Figs. 5 and 6. Aebi U, Herrmann H (2006) Impact of disease mutations on the
desmin filament assembly process. J Mol Biol 360:1031–1042
Open Access This article is distributed under the terms of the 14. Bär H, Schopferer M, Sharma S, Hochstein B, Mücke N,
Creative Commons Attribution License which permits any use, dis- Herrmann H, Willenbacher N (2010) Mutations in Desmin’s
tribution, and reproduction in any medium, provided the original carboxy-terminal ‘‘Tail’’ domain severely modify filament and
author(s) and the source are credited. network mechanics. J Mol Biol 397:1188–1198
15. Bär H, Sharma S, Kleiner H, Mücke N, Zentgraf H, Katus HA,
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