HGNC Approved Gene Symbol: DES
SNOMEDCT: 1208615009, 770627003;
Cytogenetic location: 2q35 Genomic coordinates (GRCh38): 2:219,418,377-219,426,734 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 2q35 | Cardiomyopathy, dilated, 1I | 604765 | Autosomal dominant | 3 |
| Myopathy, myofibrillar, 1 | 601419 | Autosomal dominant; Autosomal recessive | 3 | |
| Scapuloperoneal syndrome, neurogenic, Kaeser type | 181400 | Autosomal dominant | 3 |
Desmin is the muscle-specific member of the intermediate filament (IF) protein family. It is one of the earliest myogenic markers, both in heart and somites, and is expressed in satellite stem cells and replicating myoblasts. In mature striated muscle, desmin IFs form a 3-dimensional scaffold that appears to extend across the diameter of the myofibril. Desmin IFs surround the Z discs and link the entire contractile apparatus to the sarcolemmal cytoskeleton, cytoplasmic organelles, and nucleus (summary by Kouloumenta et al., 2007).
Li et al. (1989) determined that the DES gene encodes a 468-amino acid protein that shares structural features with other intermediate filament proteins, including helical domains, a stretch of heptad repeats, and the positions of linkers. Northern blot analysis detected a 2.2-kb transcript in striated skeletal muscle, uterine smooth muscle, and cultured striated muscle cells.
From a human muscle biopsy, Vicart et al. (1996) cloned and sequenced the DES gene, which encodes a 469-amino acid protein with a molecular mass of 53 kD. The head domain of desmin, comprising residues 1 to 82, has several putative phosphorylation sites, and the rod domain, comprising residues 83 to 423, contains primarily conserved hydrophobic amino acids.
Tidball (1992) found that desmin was codistributed with actin thin filaments within the cellular processes of myotendinous junctions in frog skeletal muscle. Desmin appeared to mediate attachments between the terminal Z disc and the junctional membrane, as well as linking Z discs in series in each sarcomere. In contrast to other cytoskeletal proteins, desmin was located deep in the cellular processes within the filamentous core 30 nm or more from the membrane. Tidball (1992) concluded that desmin provides attachments between the terminal Z disc and membrane-associated proteins to form a force-transmitting system that parallels the thin filaments at myotendinous junctions.
Kusubata et al. (1993) found that serine/threonine phosphorylation in the head domain of chicken desmin by Cdc2 kinase (116940) induced a transition toward the depolymerization of desmin filaments.
By yeast 2-hybrid analysis of a human heart cDNA library, Kouloumenta et al. (2007) found that the N-terminal domain of mouse desmin interacted with the C terminus of human myospryn (CMYA5; 612193). Reciprocal coimmunoprecipitation experiments and protein pull-down assays with in vitro-translated proteins confirmed direct interaction. Deletion analysis revealed that desmin bound the C-terminal SPRY domain of myospryn. Confocal microscopy of cultured unfused primary mouse cardiomyocytes revealed that the 2 proteins colocalized in a punctate pattern at the nuclear periphery. Western blot analysis of immunoprecipitates of adult mouse heart showed that desmin associated with the lysosome biogenesis complex components dysbindin and pallidin, possibly via its interaction with myospryn. In adult mouse hearts, desmin and myospryn colocalized at intercalated discs.
Li et al. (1989) determined that the DES gene contains 9 exons and spans about 8.4 kb. Intronic sequences contain 4 AluI repetitive elements, and the promoter region is G rich.
Locus control regions (LCRs) are transcriptional regulatory elements, like CpG islands, that establish a transcriptionally competent open chromatin structure. Unlike CpG islands, LCRs have invariably been found linked with tissue-specific genes. Tam et al. (2006) identified a muscle-specific LCR linked to the DES gene. The DES LCR is a complex multicomponent element located within 18 kb 5-prime of the DES transcriptional start site. Tam et al. (2006) identified 2 genes immediately downstream of DES, SPEG and APEG1 (see 615950), that are also preferentially expressed in muscle, and they suggested that the DES LCR may form a functional expression module involved in regulating expression of all 3 genes.
By use of cDNA clones of desmin in somatic cell hybrids, Quax et al. (1985) assigned the DES gene to chromosome 2. By in situ hybridization, Viegas-Pequignot et al. (1989) localized the gene to 2q35.
In the mouse, Jankowski and Gumucio (1995) demonstrated that the genes for tensin (600076), villin (193040), and desmin are closely linked on chromosome 1.
Myofibrillar Myopathy 1
Goldfarb et al. (1998) reported 2 families with desmin-related cardioskeletal myopathy (MFM1; 601419) associated with mutations in the highly conserved C-terminal portion of the desmin rod domain. A heterozygous (125660.0001) mutation was found in a family with an adult-onset skeletal myopathy and mild cardiac involvement. Compound heterozygosity for 2 other desmin mutations (125660.0002; 125660.0003) was detected in a second family with a childhood-onset aggressive course of cardiac and skeletal myopathy.
Dalakas et al. (2000) searched for mutations in the desmin gene in 22 patients from 8 families with dominantly inherited myofibrillar or desmin-related myopathy and 2 patients with sporadic disease. They identified mutations in 12 patients (10 from 4 families and 2 sporadic), 7 of whom had cardiomyopathy.
Kaminska et al. (2004) studied 3 families with skeletal or cardioskeletal myopathy caused by small in-frame deletions in the desmin gene. Two Polish families with skeletal myopathy without cardiac involvement had an in-frame deletion of 3 amino acids (125660.0012) in an area known to be conserved in evolution. An affected Spanish family had a single amino acid deletion (125660.0013). Kaminska et al. (2004) showed that these small deletions disturbed the coiled-coil structure of desmin in a highly specific way.
In 4 unrelated probands with desmin-related myopathy, Bar et al. (2007) identified 3 novel mutations in the DES gene (see, e.g., 125660.0015) located in the non-alpha-helical C-terminal tail domain of the protein. All had severe skeletal and cardiac muscle involvement. Functional expression studies of these and other tail domain pathogenic mutations revealed that different mutations in the tail region had different functional effects. Although some mutant proteins were unable to assemble into filaments, most formed filaments with altered viscometric properties and/or impaired ability to assemble properly with wildtype desmin. Bar et al. (2007) suggested that desmin tail mutations can affect multiple pathways, including mechanochemical signaling, intracellular transport, and interactions with other proteins, resulting in distinct cellular malfunctions and variable clinical phenotypes.
In affected members of 2 distantly related Dutch families segregating autosomal dominant desmin-related myopathy with a highly heterogeneous clinical picture, varying from isolated dilated cardiomyopathy to more generalized skeletal myopathy and mild respiratory problems, Bergman et al. (2007) identified heterozygosity for a missense mutation in the DES gene (S13F; 125660.0019) that was not present in unaffected family members.
In 4 affected members of a 2-generation Chinese family with desmin-related myopathy, Pica et al. (2008) identified heterozygosity for the S13F mutation in the DES gene.
Van Tintelen et al. (2009) restudied the Dutch kindred with MFM1 reported by Bergman et al. (2007) and expanded it to include 3 distantly related families. The authors described 2 more affected Dutch families whose ancestors could be traced to the same small, poorly populated region in which the common ancestral couple of the large Dutch kindred had lived. All 27 affected individuals were heterozygous for the DES S13F mutation; based on haplotype analysis, the mutation was estimated to be between 220 and 495 years old. Immunofluorescence analysis of patient myocardia showed normal amounts of the major desmosomal proteins, but intercalated discs were more convoluted and elongated and had a zigzag appearance compared to controls.
Pinol-Ripoll et al. (2009) reported a female patient with recurrent episodes of syncope from infancy and an aggressive course leading to the devastation of cardiac, skeletal, and smooth musculature and death from cardiac failure at age 20 years, in whom they identified homozygosity for a 21-bp deletion in the desmin gene (125660.0004). Pinol-Ripoll et al. (2009) stated that this was the first reported case of infantile-onset desmin-associated cardiopathy, and noted that their patient had the same mutation previously identified by Munoz-Marmol et al. (1998) in a 15-year-old boy.
In a Dutch patient with desmin-related myopathy and arrhythmogenic right ventricular cardiomyopathy (ARVC), Otten et al. (2010) identified heterozygosity for a missense mutation in the DES gene (N342D; 125660.0020).
In affected members of a large Swedish family segregating autosomal dominant MFM1 and ARVC, Hedberg et al. (2012) identified a heterozygous P419S mutation (125660.0017) in the DES gene.
In 2 Turkish sibs, born of consanguineous parents, with what the authors called autosomal recessive limb-girdle muscular dystrophy (LGMD2R), Cetin et al. (2013) identified a homozygous splice site mutation in the DES gene (125660.0018). LGMD2R was later reclassified as a form of myofibrillar myopathy by Straub et al. (2018). The mutation, which was found by homozygosity mapping followed by candidate gene sequencing, segregated with the disorder and was not found in several control databases. The mutant protein was expressed in patient skeletal muscle, which had normal myofibrillar organization, but confocal laser scanning microscopy showed a disruption in binding between desmin and lamin B (LMNB1; 150340). The patients had onset in their teens or twenties of progressive proximal muscle weakness and atrophy affecting the upper and lower limbs. Neither patient had evidence of a cardiomyopathy, and muscle biopsy showed dystrophic changes without protein aggregates or myofibrillar myopathy.
Dilated Cardiomyopathy 1I
Li et al. (1999) used a candidate gene approach to identify genetic defects in 44 unrelated probands with autosomal dominant dilated cardiomyopathy. In 1 family with pure cardiomyopathy without skeletal myopathy (CMD1I; 604765), they identified a heterozygous ile451-to-met mutation in the DES gene (125660.0005). The reports of Goldfarb et al. (1998) and Li et al. (1999) suggested a distinct cardiac genotype-phenotype correlation for mutations in the DES gene.
Miyamoto et al. (2001) screened exon 8 of the DES gene in a cohort of 265 Japanese probands with dilated cardiomyopathy and identified 3 unrelated men who were heterozygous for the previously reported I451M mutation. None of the 3 patients showed any clinical evidence of skeletal muscle involvement on physical examination, and none had abnormal serum levels of creatine kinase or a myopathic pattern on electromyelogram.
Taylor et al. (2007) analyzed the DES gene in 425 probands with dilated cardiomyopathy and identified 5 missense mutations in 6 sporadic patients, 3 of which were likely pathogenic (see, e.g., 125660.0021). None of the patients had overt skeletal muscle involvement, although none had a skeletal muscle biopsy and formal neurologic assessment was not performed in most patients. Functional analysis of the 3 likely pathogenic mutations demonstrated severe disruption of desmin filament assembly.
Neurogenic Scapuloperoneal Syndrome, Kaeser Type
In a large, multigenerational kindred with scapuloperoneal weakness and atrophy (SCPNK; 181400) originally described by Kaeser (1964, 1965), Walter et al. (2007) detected a heterozygous missense mutation (125660.0016) in the DES gene in all affected members.
Wieneke et al. (2000) generated Des-null mice and found that desmin is not essential for acute tensile strength, but rather for optimal activation of intact myofibers during excitation-contraction coupling.
Li et al. (1996) developed desmin-null mice. Despite the complete lack of desmin, mutant mice developed and reproduced. Skeletal, cardiac, and smooth muscle formed in mutant mice, but morphologic abnormalities were observed in the diaphragm of adult mice. These abnormalities were characterized by disorganized, distended, and nonaligned fibers. The hearts of mutant mice presented areas of hemorrhage in which fibrosis and ischemia were observed. The absence of desmin also produced defects in smooth muscles. Li et al. (1996) concluded that desmin is not required for myogenic commitment or for myoblast fusion and differentiation of skeletal, cardiac, and smooth muscle, but it is essential to strengthen and maintain the integrity of these tissues.
Using analytical ultracentrifugation, viscometry, and time-lapse electron microscopy, Bar et al. (2005) examined how myopathy-associated mutations within the alpha-helical rod domain of mouse desmin affected distinct phases of intermediate filament assembly. Whereas 6 of the 14 mutants allowed assembly of desmin into normal filaments in vitro, the other mutants interfered with the assembly process at distinct stages, i.e., tetramer formation, unit-length filament formation, filament elongation, and intermediate filament maturation. Mutants with in vitro assembly defects yielded dot-like aggregates in transfected cells, whereas mutants that formed filaments in vitro formed seemingly normal cytoskeletal intermediate filaments following transfection into vimentin (193060)-free human adrenocortical carcinoma cells or vimentin-positive mouse fibroblasts. Bar et al. (2005) concluded that the degree of assembly defect of a mutant desmin variant in vitro does not correlate directly with disease phenotype.
By immunohistochemical analysis of wildtype and Des -/- mouse hearts, Kouloumenta et al. (2007) found that Des knockout resulted in abnormalities at the intercalated discs. In primary mouse cardiomyocytes, Des knockout resulted in mislocalization of lysosomes.
In affected members of a family with adult-onset myofibrillar myopathy-1 (MFM1; 601419) and mild cardiac involvement, Goldfarb et al. (1998) identified a heterozygous G-to-C transversion in exon 5 of the DES gene, resulting in an ala337-to-pro (A337P) substitution.
In 3 of 4 sibs affected with a severe childhood-onset form of cardioskeletal myopathy (MFM1; 601419), Goldfarb et al. (1998) identified compound heterozygosity for 2 mutations in the DES gene: a G-to-C transversion in exon 6, resulting in an ala360-to-pro (A360P) substitution, and an A-to-T transversion in exon 6, resulting in an asn393-to-ile (N393I) substitution (125660.0003). Several older unaffected members of the family who were beyond the maximal age of disease onset had 1 of these mutations; the 55-year-old mother of the affected sibs and her 54-year-old sister showed the A360P mutation, and a 66-year-old paternal uncle carried the N393I mutation.
For discussion of the asn393-to-ile (N393I) mutation in the DES gene that was found in compound heterozygous state in patients with severe childhood-onset myofibrillar myopathy-1 (MFM1; 601419) by Goldfarb et al. (1998), see 125660.0002.
In a patient with severe generalized myopathy (MFM1; 601419) reported by Ariza et al. (1995), Munoz-Marmol et al. (1998) identified a homozygous 21-bp deletion in the DES gene, predicting a mutant desmin protein lacking 7 amino acids, residues arg173 to glu179. Munoz-Marmol et al. (1998) provided functional analysis to demonstrate that this mutation severely compromised the ability of desmin to assemble into intermediate filaments in vivo and in vitro. In desmin-null mice, myofibrils are fragile upon mechanical stress, and muscle weakness develops with age. This mechanical-sensitive aspect of the phenotype was evident in the patient, who developed muscle weakness in his teens.
In a female patient who had recurrent episodes of syncope from infancy and an aggressive course leading to the devastation of cardiac, skeletal, and smooth musculature and death from cardiac failure at age 20 years, Pinol-Ripoll et al. (2009) identified homozygosity for the same 21-bp deletion in the DES gene. Her consanguineous unaffected parents were each heterozygous for the mutation. Pinol-Ripoll et al. (2009) stated that this was the youngest known molecularly identified patient with desminopathy.
In a family with autosomal dominant pure dilated cardiomyopathy (CMD1I; 604765), Li et al. (1999) identified a heterozygous C-to-G transversion at nucleotide 1353 of the DES gene, resulting in an ile451-to-met substitution. This mutation was not present in 920 control chromosomes. The residue involved is located in the carboxy tail domain of the protein, suggesting an important functional role for this region in cardiac myocytes.
Miyamoto et al. (2001) screened exon 8 of the DES gene in a cohort of 265 Japanese probands with dilated cardiomyopathy and identified 3 unrelated men who were heterozygous for the I451M substitution. None of the 3 patients showed any clinical evidence of skeletal muscle involvement on physical examination, and none had abnormal levels of creatine kinase or a myopathic pattern on electromyelogram. All 3 cases were sporadic; in the 1 family in which parental DNA was available, the mutation was shown to have arisen de novo. Haplotype analysis indicated that 2 of the men might have been ancestrally related.
In affected members of a large, 6-generation Ashkenazi Jewish family with desmin-related myopathy (MFM1; 601419) reported by Horowitz and Schmalbruch (1994), Sjoberg et al. (1999) identified what they claimed to be the first point mutation in desmin cosegregating with an autosomal dominant form of desmin-related myopathy. The leu345-to-pro mutation (L345P) in this kindred was located in an evolutionarily highly conserved position of the desmin coiled-coil rod domain important for dimer formation. L345P desmin was incapable of forming filamentous networks in transfected HeLa and SW13 cells. Sjoberg et al. (1999) concluded that the L345P mutation causes myopathy by interfering in a dominant-negative manner with the dimerization-polymerization process of intermediate filament assembly.
In a sporadic case of cardiac and skeletal myopathy (MFM1; 601419), Park et al. (2000) demonstrated heterozygosity for an arg406-to-trp (R406W) mutation in the DES gene. The mutation was not found in the patient's father, mother, or sister. Alternative paternity was excluded. Haplotype analysis indicated that the patient's father was a germline mosaic for the desmin mutation.
In a patient with cardiac and skeletal myopathy (MFM1; 601419), Park et al. (2000) identified a heterozygous A-to-G change at the +3 position of the splice donor site of intron 3 of the DES gene. Expression studies confirmed that this mutation caused deletion of exon 3.
In affected members of a large family diagnosed with autosomal dominant limb-girdle muscular dystrophy and cardiomyopathy (Messina et al., 1997), Greenberg et al. (2012) identified a heterozygous A-to-G transition in intron 3 of the desmin gene. The mutation was found after laser capture microdissection of skeletal muscle and mass spectrometry-based proteomics identified desmin as the major constituent of cytoplasmic inclusions. Initial mapping studies on this family by Messina et al. (1997) had found linkage to chromosome 6q23, and the locus was designated 'LGMD1D.' Subsequent mapping by Greenberg et al. (2012) excluded 6q23 due to absence of cosegregation of this locus with the phenotype in affected family members.
In a patient with cardiac and skeletal myopathy (MFM1; 601419), Park et al. (2000) identified a heterozygous G-to-A change at the -1 position of the splice acceptor site of intron 2 of the DES gene. Expression studies confirmed that this mutation caused deletion of exon 3.
In a patient with cardiomyopathy and distal weakness (MFM1; 601419), Sugawara et al. (2000) identified a de novo missense mutation in the DES gene: a C-to-T transition in exon 6, resulting in a leu385-to-pro (L385P) substitution in the C-terminal rod domain. The mutation was not present in the patient's parents or in 100 control subjects. The mutation caused cytoplasmic aggregation and nuclear DNA condensation and fragmentation, suggesting that mutations in this region of desmin may lead to disruption of intermediate filament structure or apoptotic cell death. The authors noted that several other mutations had been found in the C-terminal rod domain and suggested that exon 6 may be a hotspot for mutations causing desmin myopathy.
In an isolated case of desmin-related myopathy (MFM1; 601419), Goudeau et al. (2001) identified a heterozygous 1166A-C transversion in exon 6 of the DES gene, resulting in a gln389-to-pro (Q389P) substitution in the C-terminal part of the desmin rod domain. The patient was a 55-year-old male who had distal muscle weakness since the age of 40 which progressed over the next 10 years to involve proximal muscles as well as velopharyngeal and cardiac muscles. By transfection of desmin cDNA containing the patient's mutation into 3 cell types, Goudeau et al. (2001) demonstrated a dominant-negative effect on desmin filament formation.
In 2 Polish families with myofibrillar myopathy (MFM1; 601419) without cardiac involvement, Kaminska et al. (2004) found in-frame deletion of 3 amino acids which altered the heptad periodicity within a critical 2B coiled-coil segment. The 3-amino acid deletion introduced a second stutter immediately downstream of the naturally occurring stutter, thus doubling the extent of the local coiled-coil unwinding.
In a Spanish family with cardiac and skeletal myopathy (MFM1; 601419), Kaminska et al. (2004) found in-frame deletion of a single amino acid residue, asparagine-366. The patient presented with symmetric distal lower limb weakness at the age of 36 years, which progressed to involve the proximal muscles of the legs and arms. He became wheelchair-dependent at the age of 50. He died suddenly at the age of 56 years, probably from cardiac complications. The patient's mother and maternal grandmother suffered from a similar disease and also died suddenly, at the age of 60 and 63 years, respectively.
Schroder et al. (2003) reported a 40-year-old patient with distal myopathy and cardiac arrhythmia (MFM1; 601419). Patient skeletal muscle fibers showed decreased maximal rates of respiration with glutamate and malate, as well as higher amytal sensitivity, indicating an in vivo inhibition of complex I activity. The patient was found to carry a 3-bp deletion in the DES gene (720_722delGAA) leading to deletion of a single lysine at position 240 (K240del). The K240del mutation was incapable of forming a de novo desmin intermediate filament system in SW13 cells and led to disruption of the endogenous intermediate filament network and formation of pathologic protein aggregates in 3T3 cell. This mutation was reported in an erratum, in which the authors stated that the original genetic analysis was incorrect. The original reported mutation was a 1-bp insertion (5141_5143insA) predicted to lead to a truncated desmin (Lys239fsTer242).
In 3 affected members of a French family with autosomal dominant myofibrillar myopathy-1 (MFM1; 601419), Bar et al. (2007) identified a 1325C-T transition in the DES gene, resulting in a thr442-to-ile (T442I) substitution in the C-terminal tail domain. The proband had onset of proximal and distal lower limb weakness and dyspnea on exertion at age 35 years, followed by proximal upper limb weakness a year later. He had increased serum creatine kinase and became wheelchair-bound at age 44 years. He underwent tracheostomy for nocturnal ventilatory assistance at age 46 years. A year later he had a pacemaker implanted for bradyarrhythmia. Of note, the patient had repetitive episodes of diarrhea and constipation during the disease course, indicating smooth muscle involvement. His mother and 2 maternal aunts died of heart failure. A sporadic patient from Canada, who also had the mutation, developed distal muscle weakness at age 33 years and cardiomyopathy approximately 5 years later. Functional expression studies in vitro and in cell culture showed that the T442I mutant protein assembled into filaments with abnormal viscometric properties. Coexpression with wildtype desmin showed a severe disturbance of filament formation and filament-filament interaction, indicating an inability for the mutant and wildtype proteins to form mixed filaments.
In the large, multigenerational kindred with scapuloperoneal weakness and atrophy (SCPNK; 181400) originally described by Kaeser (1964, 1965), Walter et al. (2007) detected a heterozygous 1049G-C transversion in the DES gene that resulted in an arg350-to-pro (R350P) amino acid substitution in all affected members. This mutation had been described by Bar et al. (2005) in a family with mixed distal myopathy/limb girdle phenotype, presented as family 4 by Walter et al. (2007).
Bar et al. (2005) reported the effects of the R350P mutation, which resides in conserved coil 2B domain of the alpha-helical coiled-coil desmin rod domain. Transfection studies showed that R350P-mutant desmin was incapable of de novo formation of a desmin intermediate filament network in vimentin (193060)-free cells, and that it disrupted the endogenous vimentin cytoskeleton in fibroblasts. In vitro studies revealed that the assembly process of R350P-mutant desmin was already disturbed at the unit length filament level, and that further association reactions generated huge, tightly packed protein aggregates. A ratio of 1:3 (R350P to wildtype) was sufficient to effectively block the normal polymerization process of desmin intermediate filaments. Bar et al. (2005) concluded that the R350P mutation exerted a dominant-negative effect on the ordered lateral arrangement of desmin subunits.
In 7 affected members of a large Swedish family with autosomal dominant myofibrillary myopathy-1 with arrhythmogenic right ventricular cardiomyopathy (MFM1; 601419) originally reported by Melberg et al. (1999), Hedberg et al. (2012) identified a heterozygous 1255C-T transition in exon 7 of the DES gene, resulting in a pro419-to-ser (P419S) substitution in the tail region of desmin. The mutation was identified by exome sequencing and confirmed by Sanger sequencing. The phenotype in this family was characterized by variable muscle weakness associated with myopathic changes and desmin accumulation on muscle biopsy. Three patients had arrhythmogenic right ventricular cardiomyopathy, resulting in death. Initial mapping studies on this family by Melberg et al. (1999) had found linkage to chromosome 10q22, and the locus was formerly designated in OMIM as ARVD7.
In 2 Turkish sibs, diagnosed with autosomal recessive limb-girdle muscular dystrophy (LGMD2R), which was reclassified as a form of myofibrillar myopathy (MFM1; 601419) by Straub et al. (2018), Cetin et al. (2013) identified a homozygous A-to-G transition in intron 7 of the DES gene (c.1289-2A-G), resulting in a splice site mutation and the addition of 16 amino acids in the C terminus beginning from residue 428. The parents of the sibs were consanguineous. The mutation, which was found by homozygosity mapping followed by candidate gene sequencing, segregated with the disorder and was not found in several control databases. The mutant protein was expressed in patient skeletal muscle, which had normal myofibrillar organization, but confocal laser scanning microscopy showed a disruption in binding between desmin and lamin B (LMNB1; 150340), a component of the nuclear lamina. The patients had onset in their teens or twenties of progressive proximal muscle weakness and atrophy affecting the upper and lower limbs. Neither patient had evidence of a cardiomyopathy, and muscle biopsy showed dystrophic changes without protein aggregates or myofibrillar myopathy.
In affected members of 2 distantly related Dutch families segregating autosomal dominant myofibrillar myopathy-1 (MFM1; 601419) with a highly heterogeneous clinical picture, varying from isolated dilated cardiomyopathy to more generalized skeletal myopathy and mild respiratory problems, Bergman et al. (2007) identified heterozygosity for a c.38C-T transition in exon 1 of the DES gene, resulting in a ser13-to-phe (S13F) substitution within a highly conserved nonapeptide motif in the 'head' domain. The authors noted that the serine at position 13 serves as a phosphorylation site for protein kinase C (176960) and is required for appropriate dimer-dimer formation. The mutation was not found in unaffected family members or in 216 ethnically matched controls. Haplotype analysis confirmed the distant relationship between the 2 families, who resided in nearby villages.
In a 39-year-old Chinese man who presented with complete heart block and mild proximal and distal limb weakness, Pica et al. (2008) identified heterozygosity for the S13F mutation in the DES gene. His mother and 2 sibs, who were also heterozygous for the mutation, had somewhat milder limb weakness. His affected brother also reported 2 episodes of unexplained syncope, whereas his affected sister reported episodes of palpitations. The mutation was not found in his unaffected father or in 100 unrelated controls. Transfection studies in BHK21 and MCF7 cells demonstrated a fine filamentous desmin network with both mutant and wildtype DES; however, there were significantly more large accumulations of desmin material with the S13F mutant compared to wildtype.
Van Tintelen et al. (2009) restudied the Dutch kindred with MFM1 reported by Bergman et al. (2007) and expanded it to include 3 distantly related families. The authors described 2 more affected Dutch families whose ancestors could be traced to the same small, poorly populated region in which the common ancestral couple of the large Dutch kindred had lived. All 27 affected individuals were heterozygous for the S13F mutation, which was not found in 300 ethnically matched chromosomes. Based on haplotype analysis, the mutation was estimated to be between 220 and 495 years old. All affected family members demonstrated a fully penetrant yet variable, predominantly cardiologic phenotype, characterized by conduction disease at an early age and right ventricular involvement, including right bundle branch block (RBBB) and/or right ventricular tachycardias and ARVC phenocopies. Immunofluorescence of patient cardiomyocytes showed abnormal intercalated discs with a convoluted and elongated shape in a strong zigzag pattern, compared to the straight, robust lines of high intensity seen in control myocardia. These highly irregular and twisted intercalated discs were also observed on electron microscopy; however, Z discs appeared to be aligned.
In a Dutch patient with desmin-related myopathy and ARVC (MFM1; 601419), Otten et al. (2010) identified heterozygosity for a c.1024A-G transition in exon 6 of the DES gene, resulting in an asn342-to-asp (N342D) substitution at a highly conserved residue. The mutation was present in the patient's similarly affected brother but was not found in 300 control chromosomes.
In a man who was diagnosed with dilated cardiomyopathy (CMD1I; 604765) at age 55 years, Taylor et al. (2007) identified heterozygosity for a c.1134C-T transition in the DES gene, resulting in an arg350-to-trp (R350W) substitution at a residue within the conserved alpha-helical coil of the 2B rod domain. DNA from family members was unavailable for analysis, but the mutation was not found in 300 control chromosomes. The proband, who was negative for mutation in 6 known CMD-associated genes, had no overt skeletal muscle involvement, and creatine kinase level was normal. Immunofluorescence microscopy of transfected SW13 cells, human coronary artery smooth muscle cells, and neonatal rat cardiac myocytes expressing the R350W mutation revealed severe disruption of the normal desmin cytoskeletal architecture in the majority of transfected cells, with clumping and aggregation of antibody-positive staining cytoplasmic protein. The mutation demonstrated a dominant phenotype in the human coronary artery smooth muscle cell lines, in which constitutively expressed desmin was unable to compensate for the presence of the R350W mutant.
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