Research Article

Genetics & Molecular Medicine

The DES R415W Mutation: Clinicopathological Report of Four Patients

Sadaf Khorasanizadeh, M.D1, Qian Wu, M.D2, Marie L. Rivera-Zengotita, M.D.3 and Kevin J. Felice, D.O1*
1
Muscular Dystrophy Association Care Center, Department
of Neuromuscular Medicine, Hospital for Special Care, New
Britain, Connecticut, USA.
*
Correspondence:
Dr. Kevin Felice, Muscular Dystrophy Association (MDA) Care
2
Department of Pathology and Laboratory Medicine, University Center, Department of Neuromuscular Medicine, Hospital for
of Connecticut School of Medicine, Farmington, Connecticut, Special Care, New Britain, Connecticut 06053, USA, Tel: (860)
USA. 612-6305; Fax: (860) 612-6304; E-mail: [email protected].

Department of Pathology, Immunology and Laboratory

3
Received: 09 May 2019; Accepted: 07 June 2019
Medicine, University of Florida College of Medicine, Gainesville,
FL, USA.

Citation: Sadaf Khorasanizadeh, Qian Wu, Marie L. Rivera-Zengotita, et al. The DES R415W Mutation: Clinicopathological Report
of Four Patients. Genet Mol Med. 2019; 1(1): 1-6.

ABSTRACT
The myofibrillar myopathies are a heterogeneous group of genetic disorders characterized pathologically by the
disruption of myofibrils and accumulation of degradation products in intracellular inclusions. Most patients present
with progressive limb muscle weakness – distal, proximal or both. Cardiomyopathy – dilated or hypertrophic – can
be an isolated feature or may develop concurrently with the skeletal myopathy. Mutations in the DES gene account
for approximately 7% of genetically-determined myofibrillar myopathies. DES encodes for the intermediate
filament protein desmin which is an essential component of the extra-sarcomeric cytoskeleton in cardiac, skeletal
and smooth muscle cells. Since the first report of DES gene mutations as a cause of a familial and skeletal myopathy
in two families in 1998, 126 pathogenic mutations have been documented – including 24 involving the tail domain.
The tail domain mutation, DES R415W, was previously described in a 30-year-old patient with leg weakness. Over
the past 10 years, we have diagnosed and cared for four patients with progressive skeletal myopathy and muscle
histopathology consistent with myofibrillar myopathy – all harboring the DES R415W mutation. In this report, we
describe the clinicopathological findings in these four patients. In summary, we report four patients with the DES
R415W mutation. This tail domain mutation causes a late-onset myopathy primarily affecting the lower extremities.
Respiratory muscle weakness, mild hyperCKemia, and sensory neuropathy – but not overt cardiac involvement –
are associated features.

Keywords KY, TRIM63 – have been implicated in causing myofibrillar

Myopathy, Muscular dystrophy, Myofibrillar myopathy, Desmin myopathy [4]. In addition, other gene disorders – PLEC, TTN,
myopathy, DES gene. FHL1, ACTA1, HSPB8, DNAJB6 – have also been associated
with myofibrillar histopathology, and upwards of 50% of reported
Introduction cases have eluded a specific genetic diagnosis [5].
The myofibrillar myopathies are a heterogeneous group of genetic
disorders characterized pathologically by disruption of myofibrils Mutations in the DES gene account for approximately 7%
and accumulation of degradation products in intracellular of genetically-determined myofibrillar myopathies [6]. DES
inclusions [1-3]. Most patients present with progressive limb encodes for the intermediate filament protein desmin which is
muscle weakness – distal, proximal or both. Cardiomyopathy an essential component of the extra-sarcomeric cytoskeleton
– dilated or hypertrophic – can be an isolated feature or may in cardiac, skeletal and smooth muscle cells. Mutations in DES
develop concurrently with the skeletal myopathy. Other common on chromosome 2q35 cause autosomal dominant, autosomal
phenotypic features include length-dependent sensorimotor axonal recessive, and sporadic skeletal myopathies, cardiomyopathy or
polyneuropathy and chest wall/diaphragmatic muscle weakness both with marked phenotypic variability – including myofibrillar
leading to chronic respiratory insufficiency. Thus far, ten genes – myopathy (MFM) (aka, desmin-related myopathy, desminopathy),
DES, CRYAB, SEPN1, LDB3, MYOT, FLNC, BAG3, TRIM54, limb-girdle muscular dystrophy, and dilated and hypertrophic
Genet Mol Med, 2019 Volume 1 | Issue 1| 1 of 6
cardiomyopathy [7]. Since the first description of desmin-related dermatitis. Family history was remarkable for late-onset weakness
myopathy by Goldfarb in 1998, 126 mutations in the DES gene and gait difficulties in his deceased father and older sister.
have been categorized including the case of a 30-year-old patient
with leg weakness who harbors the R415W mutation [8-10]. Over Exam was remarkable for a steppage-pattern gait. He was unable
the past 10 years, we have diagnosed and cared for four patients to stand on heels or tiptoes. He needed to push-off with both
with a progressive skeletal myopathy and muscle histopathology hands in order to arise from a chair. There were mild pes cavus
consistent with myofibrillar myopathy – all harboring the DES foot deformities and tight heel cords, and prominent atrophy of
R415W mutation. In this report, we describe the clinicopathological foot and anterior foreleg muscles. Weakness was restricted to
findings in these four patients. the lower extremities, affecting hip flexors (MRC grade 3), knee
extensors and flexors (MRC grade 4), and foot and toe extensors
Material and Methods (MRC grade 2). There was no myotonia. Ankle jerks were absent
Clinical exams and laboratory tests while other myotatic reflexes were normal. Sensory exam revealed
This is a case study. The clinical exams and all investigations were mildly decreased perception of vibration and pin prick sensations
performed with the informed consent of the patients for diagnostic in the toes and feet. Toe position sensation was intact.
purposes. The costs for all testing were funded by the patient’s
health care insurance providers. Creatine kinase was 422 units/L (normal, <175). Complete blood
count, chemistry panel, fasting blood glucose, thyroid function
Muscle biopsy studies studies, serum protein electrophoresis, immunofixation, and
Muscle biopsies for patients 1-3 were processed and analyzed at the vitamin B12 level were normal. Pulmonary function test revealed
Pathology Laboratory at the University of Connecticut (QW) and a forced vital capacity of 1.81 L (35% of predicted). Chest x-ray
for patient 4 at the University of Florida (MLRZ). Muscle tissue was normal. Electrocardiogram and echocardiogram were normal.
was obtained in open biopsy, snap frozen into the liquid phase Nerve conduction studies showed low-amplitude sural sensory
of isopentane, previously cooled in liquid nitrogen. Transverse nerve action potentials. Other sensory and motor nerve conduction
cryostat sections were cut at 10 μm thickness and stained by studies were normal. Concentric needle electromyography
hematoxylin and eosin, modified Gomori trichrome, NADH- showed increased insertional activity, sustained fibrillations and
tetrazolium reductase (NADH-TR), succinate dehydrogenase, positive sharp waves, and increased (early) recruitment of small
Congo red, periodic acid Schiff, cytochrome c oxidase according polyphasic motor unit action potentials in a diffuse pattern –
to standard protocols. Immunohistochemical analyses of muscle abnormalities were particularly prominent in clinically weak
biopsy sections were performed with monoclonal primary muscles (e.g., tibialis anterior). Electromyography was consistent
antibodies against desmin, fast and slow myosin, dystrophin (rod, with a diffuse myopathy and concurrent length-dependent sensory
C-terminus and N-terminus domains), dysferlin, merosin, emerin, neuropathy. Muscle biopsy of the right gastrocnemius showed
alpha- and gamma-sarcoglycan, and calveolin-3 using standard marked variability in myofiber size, occasional necrosis and
techniques. Samples for electron microscopy were fixed in 4% myophagocytosis, increased internalized nuclei, rare pyknotic
glutaraldehyde and processed according to standard procedures. nuclear clumps, increased endomysial fibrosis, sarcoplasmic
masses on hematoxylin-eosin and Gomori trichrome stains, core-
Genetic studies like lesions on NADH-TR stains, desmin-positive aggregates
DNA testing on immunostains, and granulofilamentous material on electron
Next-gen DNA sequencing panels were performed by several microscopy (Figure 1). Genetic testing disclosed a heterozygous
commercial reference labs including Prevention Genetics R415W mutation (c.1243C>T nucleotide substitution) in exon 6
(Marshfield, Wisconsin, USA) for patient 1, Eurofins Clinical of the DES gene.
Diagnostics (Tucker, Georgia, USA) for patient 2, Emory Genetics
(Decatur, Georgia, USA) for patient 3, and GeneDx (Gaithersburg, Patient 2
Maryland, USA) for patient 4. This 62-year-old right-handed woman is the sister of patient 1. She
noted progressive leg weakness and gait difficulties for the past
Case Reports 12 years. She required a cane about 10 years prior. Leg weakness
Patient 1 slowly progressed over the ensuing years to the point that she
This 53-year-old man presented with progressive bilateral foot became bedbound 2 years prior to our evaluation. She reported
drop and gait difficulties. Twelve years prior, he was found to have recurrent pneumonia for many years, and, over last 5 years, had
restrictive lung disease during a screening pulmonary function test 1-3 bouts of pneumonia per year. Other medical problems include
which was required for his employment as a volunteer firefighter. diabetes for 20 years and coronary artery disease requiring a left
Five years prior, he began to notice increasing shortness of anterior descending artery stent.
breath with exertion and gait difficulties with occasional falls.
He also noted mild numbness and tingling in his toes and feet. On exam, she was bedbound and morbidly obese. Cranial nerve
Gait problems progressed to the point that he required bilateral exam showed mild left upper eyelid ptosis. Strength testing revealed
ankle-foot orthoses for severe foot drop. Other medical problems mild weakness of proximal upper extremity muscles (MRC grade
included pre-diabetes, hypertension, nephrolithiasis, and seborrheic 4) and severe diffuse lower extremity muscle weakness, especially
Genet Mol Med, 2019 Volume 1 | Issue 1| 2 of 6
of hip flexors and foot dorsiflexors (MRC 1-2). Lower extremity sensory symptoms. She noted increasing shortness of breath
myotatic reflexes were absent and other reflexes were hypoactive. with exertion and utilized nocturnal continuous positive airway
Sensory exam revealed decreased vibration and proprioception device for obstructive sleep apnea. Past medical history was also
at the toe and ankle level, and decreased pin prick sensation remarkable for pulmonary and systemic hypertension, glaucoma,
affecting the feet and ankles. Pulmonary function tests, EKG and atrial fibrillation, pacemaker placement, hyperlipidemia,
echocardiogram, and lab test results were not available. gastroesophageal reflux disease, and late-onset cataracts. She
had never taken statin or myotoxic medications. She was born
Muscle biopsy showed protein aggregates on Gomori trichrome, in Philadelphia, Pennsylvania and of German ancestry. Family
granulofilamentous aggregates on electron microscopy, and history was remarkable for father dying at age 65 years from a
increased immunoreactivity on desmin stain (Figure 1). Next- myocardial infarction. Her mother died at age 63 years of unclear
Gen custom muscular dystrophy panel (35 genes) disclosed cause. Exam was remarkable for slow and unsteady gait with
a heterozygous R415W mutation (c.1243C>T nucleotide slightly stooped posture, genu valgum, and Trendelenburg pattern.
substitution) in exon 6 of the DES gene. Excluded were other She was unable to stand on heels or tiptoes. She needed to push-
potential gene disorders associated with myofibrillar pathology off with both hands in order to arise from a chair. Cranial nerve
including MYOT, TTN, PLEC and FHL1. exam showed mild partial bilateral upper eyelid ptosis but was
otherwise normal. Strength testing revealed weakness of arm
abductors, hip flexors, and foot dorsiflexors (MRC grade 4). There
was no myotonia. Ankle jerks were absent and other myotatic
reflexes were hypoactive. Sensory exam revealed mildly decreased
perception of vibration and pin prick sensations in the toes and
feet. Toe position sensation was intact.

Creatine kinase was 113 units/L (normal, <135). Complete

blood count, chemistry panel, fasting blood glucose, thyroid
function studies, serum protein electrophoresis, immunofixation,
and vitamin B12 level were normal. Pulmonary function test
revealed a forced vital capacity of 1.68 L (62% of predicted).
Electrocardiogram showed a paced rhythm and echocardiogram
showed mild left ventricular hypertrophy, and normal ejection
fraction. MRI of the lumbosacral spine showed active disc disease
with mild to moderate neural canal stenosis and neural foraminal
narrowing as well as atrophy of paraspinal muscles bilaterally.
Nerve conduction studies showed low amplitude sural sensory
nerve action potentials, and peroneal/extensor digitorum brevis
and tibial/abductor hallucis compound muscle action potentials.
Other sensory and motor nerve conduction studies were normal.
Concentric needle electromyography showed a mixed pattern
with increased insertional activity, sustained fibrillations and
positive sharp waves, and decreased recruitment of large motor
unit action potentials in distal muscles of the lower extremity; and
increased (early) recruitment of small polyphasic motor unit action
potentials in proximal muscles of the upper and lower extremities.
Electromyography was consistent with a proximal myopathy and
concurrent length-dependent sensorimotor polyneuropathy.
Figure 1: Muscle histopathology from patient 1 (A,B,C), patient 2 (D,E,F),
patient 3 (G,H), and patient 4 (I,J,K,L) showing protein aggregates (A,G Muscle biopsy of the left vastus lateralis showed moderate
[H&E], D [Gomori trichrome]), moth-eaten fibers (B [NADH-TR]), variability in myofiber size, rare regenerating myofibers, slightly
granulofilamentous aggregates (C,F [electron microscopy]), increased smaller type I myofibers, rare pyknotic nuclear clumps, and
immunoreactivity (E,H,K,L [desmin], dystrophic changes (I [H&E]), and desmin-positive aggregates on immunostains. Electron microscopy
rimmed vacuoles (J [Gomori trichrome]). did not reveal vacuoles or inclusions. Immunohistochemical stains
for dystrophin, dysferlin, alpha-sarcoglycan, gamma-sarcoglycan,
Patient 3 emerin, merosin, and caveolin-3 were normal (Figure 1). Next-
This 83-year-old woman presented with progressive leg weakness Gen custom muscular dystrophy panel (35 genes) disclosed
and gait difficulties for the past 20 years. She had required a a heterozygous R415W mutation (c.1243C>T nucleotide
rolling walker for the past 2 years to assist with ambulation. She substitution) in exon 6 of the DES gene. Excluded were other
noted occasional low back pain – otherwise, she denied pain or potential gene disorders associated with myofibrillar pathology
Genet Mol Med, 2019 Volume 1 | Issue 1| 3 of 6
including MYOT, TTN, PLEC and FHL1. antibody test, and vitamin B12 level were normal. Pulmonary
function test revealed a forced vital capacity of 2.99 L (62% of
Patient 4 predicted). MRI of the lumbosacral spine reported diffuse multi-
This 58-yo man was referred for 5 years of progressive bilateral level degenerative changes without significant canal or foraminal
foot drop and gait difficulties. He initially noticed difficulty stenosis. Nerve conduction studies were normal. Concentric needle
standing on his heels. Over time, he developed a steppage-pattern electromyography showed increased insertional activity, sustained
gait, requiring bilateral ankle-foot orthoses. He had problems fibrillations and positive sharp waves, and increased (early)
climbing stairs and arising from the floor. He noted occasional recruitment of small polyphasic motor unit action potentials in
muscle cramps, but otherwise denied pain or sensory symptoms. a diffuse pattern – abnormalities were particularly prominent in
He denied hand or arm weakness. Prior to the onset of symptoms, clinically weak muscles. Electromyography was consistent with a
he was always physically strong and active. He recalled large calf diffuse myopathy.
muscles since childhood. Prior neurologic evaluation suggested
a lower motor neuron disease as the diagnosis, probably a distal Muscle biopsy of the left gastrocnemius showed marked
spinal muscular atrophy or hereditary motor neuropathy. Past variability in myofiber size, occasional necrosis and
medical history was remarkable for hyperlipidemia, mitral valve myophagocytosis, increased internalized nuclei, rare pyknotic
prolapse, and erectile dysfunction. He was a sober alcoholic for 20 nuclear clumps, increased endomysial fibrosis, sarcoplasmic
years. He never took statin medications. He was born and resided masses on hematoxylin-eosin and Gomori trichrome stains, core-
in US. His father died at age 74 years from cardiac disease. He was like lesions on NADH-TR stains, desmin-positive aggregates
of Scottish ancestry. His mother, aged 87 years, was in a nursing on immunostains, and granulofilamentous material on electron
home. She had recently completed a course of radiation therapy microscopy. Immunohistochemical stains for dystrophin, dysferlin,
for lung cancer. She was of Dutch-Irish ancestry. Patient’s older and the sarcoglycans (alpha, beta, delta, and gamma) were normal
sister and two daughters were in good health. To his knowledge, (Figure 1). Next-Gen custom muscular dystrophy panel (80
there was no known family history of neuromuscular disease. genes) disclosed three variants including a heterozygous R415W
mutation (c.1243C>T nucleotide substitution) in exon 6 of the DES
Exam was remarkable for a steppage-pattern gait. He was unable gene, heterozygous P545R mutation (c.1634C>T substitution)
to stand on heels or tiptoes. He was able to arise from a chair and in exon 4 of the BAG3 gene, and heterozygous N140S mutation
perform a deep knee bend. There was prominent atrophy of foot (c.419A>G substitution) in exon 3 of the SGCB gene. The report
and anterior foreleg muscles, and pseudohypertrophy of bilateral also documented the DES gene substitution to occur at a position
calf muscles (Figure 2). Weakness was restricted to the lower that is conserved across species with in silico analysis predicting
extremities, affecting foot and toe extensors (MRC grade 2), and the variant to be “probably damaging” to protein structure and
plantar flexors (MRC grade 3). There was no myotonia. Ankle function. The BAG3 gene substitution occurred at a position
jerks were hypoactive while other myotatic reflexes were normal. that is not conserved, and in silico analysis was inconsistent in
Sensory exam revealed mildly decreased perception of vibration predictions about the pathogenicity of this variant. A second
sensation in the toes and feet. Toe position sensation was intact. SGCB gene mutation was not identified. Excluded were other
potential gene disorders associated with myofibrillar pathology
including ACTA1, CRYAB, FHL1, MYOT, SEPN1, DNAJB6,
FLNC, PLEC, LDB3, and TTN.

Discussion
This report provides strong clinicopathological evidence for the
causative role of the DES R415W mutation in the myopathic
weakness of our four patients. Inheritance pattern was autosomal
dominant for patients 1 and 2, and dominant or sporadic for patients
3 and 4. All developed late-onset weakness – primarily of the
lower extremities – with distal and proximal muscle involvement.
For patients 1, 2, and 4, the presentation of bilateral foot drop and
steppage-pattern gait is a common feature for the myofibrillar
myopathies including those due to DES gene mutations. The
calf muscle pseudohypertrophy for patient 4 seemed to be a
novel feature for desmin-related myopathy, as we are not aware
of a previously reported association. Clinical and EMG findings
Figure 2: Photograph of patient 4 showing calf muscle pseudohypertrophy. implicated concurrent sensory polyneuropathy for patients 1, 2,
and 3. However, for patients 1 and 2, the neuropathy may have
Creatine kinase was 447 units/L (normal, <173). Complete blood resulted from longstanding diabetes mellitus. The symptoms
count, chemistry panel, fasting blood glucose, thyroid function of dyspnea along with the reduced FVC values – implicating
studies, serum protein electrophoresis, immunofixation, GM1 respiratory muscle weakness, and normal to mildly elevated
Genet Mol Med, 2019 Volume 1 | Issue 1| 4 of 6
CK values were features previously reported in myofibrillar mutation and wild-type protein to form mixed filaments [13,14].
myopathies. Patients 1, 2 and 4 did not have symptomatic cardiac Based on clinical and experimental data thus far, it is likely that
involvement or abnormalities noted on cardiac testing. The tail mutations lead to altered interactions of the desmin tail domain
cardiologist for patient 3 noted that she had AV node ablation with other components of the myoblast cytoskeleton.
and pacemaker placement for control of persistent tachycardia
related to atrial fibrillation. However, echocardiogram showed no The pathogenicity of the DES R415W is suspect for several reasons.
evidence of systolic or diastolic cardiomyopathy, and patient had a First, this variant has been observed in a 30-year old individual with
normal left ventricular ejection fraction. Whether or not the atrial a lower limb skeletal myopathy [9,10]. Unfortunately, a detailed
fibrillation was due to desmin-related cardiac involvement remains description of this case was not provided. Second, this variant has
uncertain. Desmin-related myopathy was further supported by not been observed in approximately 6,500 individuals of European
the muscle histopathology and electron microscopy – showing and African American ancestry in the NHLBI Exome Sequencing
changes consistent with myofibrillar myopathy, and desmin Project, indicating that it is not a common benign variant in these
immunohistochemistry – showing increased reactivity. Finally, populations [15]. Third, R415W variant is a non-conservative
comprehensive DNA analyses identified the heterozygous DES amino acid substitution, which is likely to impact secondary
R415W mutation for all four patients, and excluded other gene protein structures as these residues defer in polarity, charge, size
disorders. For patient 4, we could not absolutely exclude the and other properties. This substitution occurs at a position that is
BAG3 P545R mutation as a primary or contributing pathogenic conserved across species and in silico analysis predicts this variant
variant. Points that disfavor its pathogenic role include absence is probably damaging to the protein structure/function (GeneDx,
of previously reported cases harboring this mutation, inconsistent Gathersburg, Maryland, USA). Fourth, missense variants in the
in silico analysis (GeneDx, Gathersburg, Maryland, USA), and same (R415Q) and nearby residues (E413K, P419S) have been
the late-onset and relatively mild phenotype – somewhat atypical reported in the Human Gene Mutation Database in association
clinical features of the Bag3opathies [1]. with DES-related disorders, supporting the functional importance
of this region of the protein [16-19]. Finally, the pathogenicity of
The desmin protein is a major intermediate filament and essential the more commonly-reported variant, R454W, sharing the same
component of the extra-sarcomeric cytoskeleton in muscle cells. non-conservative amino acid substitution in the tail domain,
Desmin is expressed in cardiac, skeletal, and smooth muscle. has been shown to assemble aberrantly shortened and irregular
Desmin interacts with other proteins to form a continuous filamentous structures and prominent aggregates in experimental
cytoskeletal network that maintains a spatial relationship between in vitro assays [13,14]. Although not proven with similar assays to
the contractile apparatus and other structural elements of the our knowledge, it is likely that the R415W mutation would have a
cell, therefore, providing maintenance of cellular integrity, force similar negative affect on filament formation.
transmission, and mechanochemical signaling [3]. Human desmin
is encoded by the single-copy DES gene localized on 2q35. Although the DES R415W is the likely cause for the
The DES gene contains nine exons within an 8.4-kb region and clinicopathological findings in the patients described, our study has
encodes 470 amino acids. DES is organized into three domains several limitations. First, ours is a clinicopathological study only
including a highly conserved α-helical core flanked by globular without experimental in vitro analyses of the R415W mutation.
N- and C-terminal structures known as the head and tail domains, Second, this study lacks extensive clinical and genetic testing in
respectively [11]. The helical rod is further subdivided into four other at-risk family members – including living parents (patient
consecutive helical segments – referred to as 1A, 1B, 2A and 2B – 4), siblings (patient 4), and children (patients 3 and 4). Third, our
connected by three non-helical linkers. Since the first report of DES patients had extensive DNA studies – but not all of the potential
gene mutations as a cause of a familial and skeletal myopathy in two genes causing or associated with myofibrillar pathology were
families in 1998, 126 pathogenic mutations have been documented analyzed. Fourth, although we did not identify definite cardiac
– including 99 missense and nonsense, 11 small deletions, 9 involvement abnormalities for our patients, it is possible that
splicing, 3 small indels, 2 small insertions, 1 large deletion, and more sensitive testing including cardiac MRI would have shown
1 complex rearrangement [8,12]. Mutations have been described subclinical abnormalities, e.g., myocardial scarring. Despite these
in all three DES gene domains – including the tail domain which limitations, we believe that the clinicopathological evidence is
extends from codons 410 to 470. Of the 24 tail domain mutations, supportively strong.
15 have been associated with the skeletal myopathy phenotype and
9 with cardiomyopathy. How tail domain mutations cause cardiac In summary, we report four patients with the DES R415W
and skeletal muscle dysfunction is unclear. The tail domain lacks mutation. This tail domain mutation causes a late-onset myopathy
the heptad repeat pattern as noted in the rod domain and is involved primarily affecting the lower extremities. Respiratory muscle
mainly in interacting with other cytoskeletal proteins to establish weakness, mild hyperCKemia, and sensory neuropathy – but not
a cytoplasmic intermediate filament network [9]. Experimental in overt cardiac involvement – are associated features.
vitro analyses using transfected myoblasts and viscometric assays
have shown that several tail mutations including R454W cause a Funding
severe disturbance of filament formation competence and filament- This research did not receive any specific grant from funding
filament interactions, indicating an inherent incompatibility of agencies in the public, commercial, or not-for-profit sectors.
Genet Mol Med, 2019 Volume 1 | Issue 1| 5 of 6
References Cardiol. 2016; 92: 93-95.
1. Selcen D. Myofibrillar myopathies. J Neuromuscul Disord. 12. Human Gene Mutation Database, https://portal.biobase-
2011; 21: 161-171. ternational.com/hgmd/pro/start.php; 2018 [accessed
2. Batonnet-Pichon S, Behin A, Cabet E, et al. Myofibrillar 20.08.18].
myopathies: new perspectives from animal models to potential 13. Bar Harald, Goudreau B, Walde S, et al. Conspicuous
therapeutic approaches. J Neuromuscul Dis. 2017; 4: 1-15. involvement of desmin tail mutations in diverse cardiac and
3. Clemen CS, Herrman H, Strelkov SV, et al. Desminopathies: skeletal myopathies. Hum Mutat. 2007; 28: 374-386.
pathology and mechanisms. Acta Neuropathol. 2013; 125: 47- 14. Brodehl A, Hedde PN, Dieding M, et al. Dual color
75. photoactivation localization microscopy of cardiomyopathy-
4. Gene Table of Neuromuscular Disorders, http://www. associated desmin mutants. J Biol Chem. 2012; 287: 16047-
musclegenetable.fr/; 2018 [accessed 01.10.18]. 16057.
5. Kley R, Olive M, Schroder R. New aspects of myofibrillar 15. NHLBI Exome Sequencing Project, http://evs.gs.washington.
myopathies. Curr Opin Neurol. 2016; 29: 628-34. edu/EVS/; 2018 [accessed 20.8.18].
6. Selcen D, Engel A. Myofibrillar myopathy. Gene Reviews. 16. Olive M, Armstrong J, Miralles F, et al. Phenotypic patterns
2012. of desminopathy associated with three novel mutations in the
7. van Spaendonck KY, van Hessem L, Jongbloed JDH, et al. desmin gene. Neuromuscul Dis. 2007; 17: 443-450.
Desmin-related myopathy. Clin Genet. 2011; 80: 354-66. 17. Pruszczyk P, Kostera-Pruszczyk A, Shatunov A, et al.
8. Goldfarb LG, Park KY, Cervenakova L, et al. Missense Restrictive cardiomyopathy with atrioventricular conduction
mutations in desmin associated myopathy with familial block resulting from desmin mutation. Internal J Cardiol.
cardiac and skeletal myopathy. Nat Genet. 1998; 19: 402-403. 2007; 117: 244-253.
9. Goldfarb LG, Olive M, Vicart P, et al. Intermediate filament 18. Olive M, Odgerel Z, Martinez A, et al. Clinical and
diseases: desminopathy. Adv Exp Med Biol. 2008; 642: 131- myopathological evaluation of early- and late-onset subtypes
164. of myofibrillar myopathy. Neuromuscul Dis. 2011; 21: 533-
10. Goldfarb LG, Dalakas MC. Tragedy in a heartbeat: 542.
malfunctioning desmin causes skeletal and cardiac muscle 19. Ripoll-Vera T, Zorio E, Gamez JM, et al. Phenotypic patterns
disease. J Clin Invest. 2009; 119: 1806-1813. of cardiomyopathy caused by mutations in the desmin gene.
11. Azzimato V, Genneback N, Tabish AM, et al. Desmin, A clinical and genetic study in two inherited heart units. Rev
desminopathy and the complexity of genetics. J Mol Cell Esp Cardiol. 2015; 68:1027-1038.

© 2019 Sadaf Khorasanizadeh, et al. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License

Genet Mol Med, 2019 Volume 1 | Issue 1| 6 of 6