HGNC Approved Gene Symbol: DYSF
SNOMEDCT: 718179003, 782675008; ICD10CM: G71.033;
Cytogenetic location: 2p13.2 Genomic coordinates (GRCh38) : 2:71,453,561-71,686,763 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 2p13.2 | Miyoshi muscular dystrophy 1 | 254130 | Autosomal recessive | 3 |
| Muscular dystrophy, limb-girdle, autosomal recessive 2 | 253601 | Autosomal recessive | 3 | |
| Myopathy, distal, with anterior tibial onset | 606768 | Autosomal recessive | 3 |
Dysferlin belongs to a family of genes similar to Caenorhabditis elegans ferlin. Members of this family contain a type II transmembrane domain with the majority of the protein facing the cytoplasm, and they have multiple C2 domains, which are implicated in calcium-dependent membrane fusion events (Britton et al., 2000). Dysferlin plays an important role in muscle fiber repair (Bashir et al., 1998).
Liu et al. (1998) constructed a 3-Mb PAC contig spanning the Miyoshi myopathy (MMD1; 254130) candidate region. This clarified the order of genetic markers across the area, provided 5 new polymorphic markers within it, and narrowed the locus to approximately 2 Mb. They found 5 skeletal muscle ESTs that mapped in this region. Liu et al. (1998) reported that 1 of these ESTs is located in a novel, full-length 6.9-kb muscle cDNA; they designated the corresponding protein dysferlin.
By database analysis and sequencing overlapping YAC and PAC clones on chromosome 2p associated with autosomal recessive limb-girdle muscular dystrophy-2 (LGMDR2; 253601), previously symbolized LGMD2B, Bashir et al. (1998) cloned a partial dysferlin cDNA. The deduced 1,779-amino acid protein contains 2 C2 domains and a putative transmembrane domain near the C terminus. Northern blot analysis detected a major transcript of approximately 7 kb in skeletal muscle, heart, and placenta, and more weakly in liver, lung, kidney, and pancreas. A transcript of less than 4 kb was present in brain. Analysis of specific brain regions detected the 7-kb transcript only in cerebellum and medulla. The 4-kb transcript was expressed in all brain regions except spinal cord, with highest levels in putamen. No dysferlin was detected in fetal brain. The proposed name 'dysferlin' combined the role of the gene in producing muscular dystrophy with its C. elegans homology.
Britton et al. (2000) stated that DYSF contains 2,080 amino acids. By sequence analysis, they showed that it has 6 C2 domains, a C-terminal transmembrane domain, and several calcium-binding residues conserved between C. elegans ferlin, myoferlin (MYOF; 604603), and otoferlin (OTOF; 603681).
By 5-prime RACE of adult skeletal muscle total RNA, Pramono et al. (2006) identified a splice variant of DYSF, which they called DYSF-v1, that arises from an alternate first exon. The deduced 2,081-amino acid variant differs from DYSF only in the N terminus. Northern blot analysis detected a 7.5-kb DYSF-v1 transcript in skeletal muscle, heart, spleen, small intestine, kidney, liver, placenta, and lung, and a 6-kb transcript in brain. There were also minor transcripts of 2-kb and 1.3-kb. A 7.5-kb DYSF transcript was detected in brain, heart, skeletal muscle, spleen, kidney, liver, small intestine, placenta, lung, and peripheral blood leukocytes. Variable expression of minor transcripts of about 5-, 2-, and 1.3-kb was also detected. The promoter region associated with the variant DYSF-v1 contains 2 CpG islands, a TATA box, and 2 clusters of binding sites for several transcription factors, including those involved in muscle expression.
By RT-PCR of dysferlin mRNA from blood derived from 50 individuals of Chinese, Malaysian, and Indian origin as well as of skeletal muscle samples from unrelated individuals, Pramono et al. (2009) identified alternatively spliced variants of the DYSF gene involving novel exons, i.e., exons 5a and 40a. Previously reported alternative splicing of exon 17 was also found. Long-range RT-PCR and subcloning revealed a total of 14 dysferlin transcripts derived from alternative splicing, all of which maintained an open reading frame. The study also characterized the differences in relative frequencies of these dysferlin transcripts in skeletal muscle and blood. Pramono et al. (2009) suggested that these findings may have clinical relevance in the molecular diagnosis of DYSF-related disorders.
Aoki et al. (2001) reported the genomic organization of the dysferlin gene and determined that it contains 55 exons.
Pramono et al. (2006) identified a DYSF-v1 promoter region associated with an alternative first exon located within intron 1.
Bashir et al. (1994) mapped the DYSF gene to chromosome 2p13.
Anderson et al. (1999) raised a monoclonal antibody to dysferlin and studied the expression of the protein. Immunolabeling with the antibody demonstrated a polypeptide of approximately 230 kD on Western blot analysis of skeletal muscle, and microscopy at both the light and electron microscopic levels localized dysferlin to the muscle fiber membrane. A specific loss of labeling of dysferlin was observed in patients with mutations in the DYSF gene. Furthermore, patients with 2 different frameshift mutations demonstrated very low levels of immunoreactive protein in a manner reminiscent of the dystrophin expressed in many Duchenne patients. Analysis of human fetal tissue showed that dysferlin was expressed at the earliest stages of development examined, at Carnegie stage 15 or 16 (embryonic age 5 to 6 weeks). Dysferlin is present, therefore, at a time when the limbs start to form regional differentiation. Anderson et al. (1999) suggested that lack of dysferlin at this critical time may contribute to the pattern of muscle involvement that develops later, with the onset of a muscular dystrophy primarily affecting proximal or distal muscles.
Caveolin-3 (CAV3; 601253) is a skeletal muscle membrane protein important in the formation of caveolae and in which mutations were identified in a form of dominantly inherited limb-girdle muscular dystrophy (LGMD1C), reclassified as rippling muscle disease (RMD2; 606072) by Straub et al. (2018). Matsuda et al. (2001) reported that dysferlin coimmunoprecipitates with caveolin-3 from biopsied normal human skeletal muscles. Using immunofluorescence, they found abnormal localization of dysferlin in muscles from patients with LGMD1C. Amino acid sequence analysis of the dysferlin protein revealed 7 sites that correspond to caveolin-3 scaffold-binding motifs, and 1 site that is a potential target to bind the WW domain of the caveolin-3 protein. The authors hypothesized that one function of dysferlin may be to interact with caveolin-3 to subserve signaling functions of caveolae.
In C2C5 mouse cells, Fujita et al. (2007) found that wildtype dysferlin was degraded by the ubiquitin/proteasome endoplasmic reticulum (ER)-associated degradation system (ERAD). A proteosome inhibitor induced dysferlin accumulation in the ER. In contrast, mutant dysferlin (see, e.g., W999C; 603009.0010) spontaneously aggregated in the ER and stimulated autophagosome formation by activation of the ER stress-EIF2-alpha (603907) phosphorylation pathway, as well as stimulated ER stress-induced cell death. Lysosomal protease inhibitors resulted in the accumulation of mutant dysferlin aggregates. The authors proposed 2 ERAD models for intracellular dysferlin degradation: ubiquitin/proteasome ERAD(I) and autophagy/lysosome ERAD(II). Mutant dysferlin aggregates in the ER were degraded by the autophagy/lysosome ERAD(II), as an alternative to ERAD(I), when the ERAD(I) system was impaired by mutant aggregates.
The finding that Miyoshi myopathy (MMD1; 254130) and autosomal recessive limb-girdle muscular dystrophy-2 (LGMDR2; previously symbolized LGMD2B) mapped to the same chromosomal region on chromosome 2p13 raised the possibility that they might be allelic disorders. They were in fact shown to be varying expressions of the same mutant gene; 2 large inbred kindreds whose members included both MMD1 and LGMD2B patients were described by Weiler et al. (1996) and Illarioshkin et al. (1996, 1997). Affected individuals in both pedigrees shared the same haplotype. Differences in the phenotype appeared to be due to additional modifying factors.
Liu et al. (1998) described 9 mutations in the DYSF gene (see, e.g., 603009.0001-603009.0004) in 9 families with MMD1, LGMD2B, and/or distal myopathy with anterior tibial onset (DMAT; 606768); 5 were predicted to prevent dysferlin expression. Identical mutations in the dysferlin gene can produce, they concluded, more than 1 myopathy phenotype.
Bashir et al. (1998) identified 2 homozygous frameshift mutations in the DYSF gene (603009.0005 and 603009.0006, respectively), resulting in muscular dystrophy of either proximal or distal onset in 9 families.
In patients with Miyoshi myopathy, Matsumura et al. (1999) and Aoki et al. (2001) identified several mutations in the dysferlin gene (see, e.g., 603009.0010 and 603009.0011).
Weiler et al. (1999) addressed the issue of the occurrence of both LGMD2B and Miyoshi myopathy in the same family. This had suggested that the same mutation could lead to either LGMD2B or MMD1 and that additional factors were needed to explain the development of the different clinical phenotypes. The discovery of the role of the DYSF gene in these 2 disorders made it possible to test this hypothesis. Weiler et al. (1999) reported that, in a large Canadian aboriginal kindred with both LGMD2B and MMD1 patients, all affected individuals were homozygous for a pro791-to-arg (603009.0007) mutation of dysferlin and that the mutation resulted in similar reductions of dysferlin expression in the 2 types of patients. Modifier gene(s) or additional factors must account for the differences in the clinical phenotype.
In 20 of 25 Japanese patients with a clinical diagnosis of Miyoshi myopathy, Takahashi et al. (2003) identified 16 different dysferlin mutations, 10 of which were novel.
In a review of 40 patients with dysferlinopathy, Nguyen et al. (2007) found that about 50% had typical Miyoshi myopathy or LGMD2B. Other patients had more unusual phenotypes, including mixed proximal and distal onset (35%), distal painful leg swelling without muscle weakness (10%), and asymptomatic increased serum creatine kinase (5%). The disorder could worsen rapidly, and 25% of patients were initially misdiagnosed as having polymyositis.
In patients with LGMD2B or Miyoshi myopathy, Spuler et al. (2008) identified 3 different mutations in the N terminus of the DYSF gene (603009.0017-603009.0019) that resulted in deposition of dysferlin-reactive amyloid fibrils within muscle fibers. The authors postulated that amyloid protein is a proteolytic cleavage product of dysferlin, and that the mutations destabilized the protein structure, leading to an increase in the propensity to form amyloid fibrils.
The SJL mouse strain (Festing, 1979) is susceptible to many induced autoimmune diseases such as experimental autoimmune encephalitis (EAE) and inflammatory muscle disease. Additionally, the skeletal muscle of SJL mice was shown to have an increased regenerative capacity and demonstrates the spontaneous occurrence of what was designated an 'inflammatory myopathy,' accompanied by loss of strength. By histopathologic examinations of muscles in SJL mice of different ages, Bittner et al. (1999) found features compatible with a progressive muscular dystrophy, including degenerative and regenerative changes of muscle fibers and a progressive fibrosis. Histologically, the changes were observed in mice as young as 3 weeks of age. Changes affected primarily the proximal muscle groups, whereas the distal muscles remained less affected. The morphologic alterations were associated with signs of slowly progressive muscle weakness, which Bittner et al. (1999) detected as early as 3 weeks after birth when mice were suspended by their tails. The phenotype was found to be inherited as an autosomal recessive trait and was found to map to mouse chromosome 6, in a region syntenic with human 2p13, where the DYSF gene maps. Because of this synteny, Bittner et al. (1999) studied dysferlin in these mice. They found a reduction to approximately 15% of control levels in SJL mice. They found a 171-bp deletion in the Dysf gene of SJL mice, predicted to result in removal of 57 amino acids, including most of the fourth C2 domain. The last C2 domain is conserved in other members of the fer-like gene family.
Bansal et al. (2003) generated dysferlin-null mice by targeted disruption. Although dysferlin-null mice maintain a functional dystrophin-glycoprotein complex they nevertheless develop a progressive muscular dystrophy. In normal muscle, membrane patches enriched in dysferlin can be detected in response to sarcolemma injuries. In contrast, there are subsarcolemmal accumulations of vesicles in dysferlin-null muscle. Membrane repair assays with a 2-photon laser-scanning microscope demonstrated that wildtype muscle fibers efficiently resealed their sarcolemma in the presence of calcium. Interestingly, dysferlin-deficient muscle fibers were defective in calcium-dependent sarcolemma resealing. Bansal et al. (2003) concluded that membrane repair is therefore an active process in skeletal muscle fibers, and that dysferlin has an essential role in this process.
Ho et al. (2004) generated 2 novel lines of dysferlin-deficient mice obtained by gene targeting and identification of an inbred strain bearing a retrotransposon insertion in the Dysf gene, respectively. The mutations in these mice were located at the 3-prime and 5-prime ends of the Dysf gene. Both lines of mice lacked dysferlin and developed a progressive muscular dystrophy with histopathologic and ultrastructural features that closely resemble the human disease. Vital staining with Evans blue dye revealed loss of sarcolemmal integrity in both lines of mice, similar to that seen in mdx (DMD; 300377) and Cav3-deficient mice. However, in contrast to the latter group of animals, the dysferlin-deficient mice had an intact dystrophin glycoprotein complex and normal levels of caveolin-3. Ho et al. (2004) concluded that muscle membrane disruption and myofiber degeneration in dysferlinopathy were directly mediated by the loss of dysferlin via a new pathogenic mechanism in muscular dystrophies.
Han et al. (2007) generated dysferlin-null mice and observed the development of mild cardiomyopathy that was exacerbated by stress exercise. Evans blue dye uptake was increased in dysferlin-deficient cardiomyocytes. Dysf/Dmd double-knockout mice developed early-onset cardiomyopathy. Han et al. (2007) suggested that dysferlin-mediated membrane repair is important for maintaining membrane integrity of cardiomyocytes, particularly under conditions of mechanical stress.
Chiu et al. (2009) observed that muscle regeneration was attenuated in a mouse model of dysferlinopathy, with delayed removal of necrotic fibers, an extended inflammatory phase, and delayed functional recovery. Satellite cell activation and myoblast fusion appeared normal, but there was a reduction in early neutrophil recruitment in regenerating and also needle-wounded muscle in dysferlin-deficient mice. Primary mouse dysferlinopathy myoblast cultures showed reduced cytokine release upon stimulation, indicating that the secretion of chemotactic molecules was impaired. Chiu et al. (2009) suggested an extension to the muscle membrane repair model, where, in addition to fusing patch repair vesicles with the sarcolemma, dysferlin is also involved in the release of chemotactic agents. Reduced neutrophil recruitment may result in incomplete cycles of regeneration in dysferlinopathy, which combines with the membrane repair deficit to ultimately trigger dystrophic pathology.
Glover et al. (2010) generated 3 lines of transgenic mice overexpressing low, mid, and high levels of human dysferlin compared to endogenous levels in wildtype mice. Transgenic mice with high (176-fold) levels of overexpression had muscle atrophy, failure to thrive, severe kyphosis, hind-limb atrophy and weakness, and had to be euthanized between 5 and 7 months of age. Histologic studies of muscle from high and mid (36-fold) dysferlin overexpression mice showed a non-necrotic congenital myopathy with marked reduction in fiber diameter, increased connective tissue, and centralized nuclei. Cardiac muscle was also affected and showed calcifications. These pathogenic changes correlated with increasing dysferlin overexpression. Further analysis of skeletal muscle showed selective loss of the fast type II muscle fibers and abnormal accumulation of vesicular structures at sarcolemmal membranes, although the sarcolemmal membrane was intact. Other findings included evidence of endoplasmic reticulum stress and an increase in the calcium-dependent binding protein annexin-a2 (ANXA2; 151740). These findings were distinct from abnormalities seen in dysferlin-deficient mice. Low (2-fold) levels of dysferlin overexpression were not associated with cytotoxicity in skeletal muscle. Glover et al. (2010) concluded that attempts at gene replacement therapy for dysferlin need to consider expression levels and dosage.
In a French family with Miyoshi myopathy (MMD1; 254130), Liu et al. (1998) found that affected members had a homozygous nonsense mutation in codon 605 of the DYSF gene, a CAG-to-TAG transition at nucleotide 2186 (Q605X).
In a consanguineous Spanish family in which members carried the diagnosis of distal myopathy with anterior tibial onset (DMAT; 606768), Liu et al. (1998) found that the myopathy was associated with deletion of 5966G in the DYSF gene, resulting in a frameshift. Illa et al. (2001) reported the same family in greater detail and referred to the disorder as another dysferlinopathy. Affected members of the family were homozygous for the deletion.
In an Italian family in which some members had Miyoshi myopathy (MMD1; 254130) and others had limb-girdle muscular dystrophy type 2B (LGMDR2; 253601), i.e., myopathy with either distal onset or proximal onset, respectively, Liu et al. (1998) found compound heterozygosity for 2 missense mutations in the DYSF gene: an ATG-to-GTC transition at nucleotide 4265 (I1298V) and a CGT-to-TGT transition at nucleotide 6497 (R2042C; 603009.0004).
For discussion of the arg2042-to-cys (R2042C) mutation in the DYSF gene that was found in compound heterozygous state in patients with Miyoshi myopathy (MMD1; 254130) or limb-girdle muscular dystrophy type 2B (LGMDR2; 253601) by Liu et al. (1998), see 603009.0003.
In 8 Libyan Jewish families with limb-girdle muscular dystrophy type 2B (LGMDR2; 253601), Bashir et al. (1998) found that affected individuals were homozygous for a 1-bp deletion of guanine and a C-G transversion at codon 1322 of the DYSF gene, resulting in a frameshift and premature stop codon at position 1331 (numbering based on a partial DYSF amino acid sequence). Subsequently, Therrien et al. (2006) reported the mutation as an insertion/deletion (4872delinsCCCC). In a ninth Libyan Jewish family, with a single affected member, the mutation was detected in single copy; one of the parents (who did not carry the mutation) was of Romanian origin. The 25 patients in these families showed onset of the disease between 12 and 39 years of age (mean 19.5 +/- 5 years). All had lower limb involvement on average 9 years before upper limb symptoms. Thirteen patients (52%) presented with distal lower limb muscle weakness, mostly of the gastrocnemius, with some complaining of transient calf enlargement. Intrafamilial variability was seen in the distribution of muscle weakness. Only 6 patients had lost the ability to walk independently; all of these were older than 35 years. Muscle biopsy showed chronic myopathic changes, and creatine kinase was elevated 10 to 25 times the normal rate in all affected individuals.
In 2 Italian sisters with severe LGMDR2, Sinnreich et al. (2006) identified homozygosity for the insertion/deletion mutation in the DYSF gene, which they characterized as a 1-bp deletion (4872delG) and a 4876G-C transversion, that was previously reported by Bashir et al. (1998). Each parent was heterozygous for the insertion/deletion mutation. The girls had onset in the second decade of proximal muscle weakness and wasting. Their 70-year-old mother, who had had mild proximal weakness since her forties, was compound heterozygous for the indel mutation and a splice site mutation (603009.0016).
In a Palestinian Arab family described by Mahjneh et al. (1992), Bashir et al. (1998) demonstrated that autosomal recessive limb-girdle muscular dystrophy type 2B (LGMDR2; 253601) resulted from a 23-bp insertion at codon 1386 in the DYSF gene. The insertion represented a tandem duplication resulting from replication slippage and was predicted to result in frameshift and premature termination at codon 1427 (numbering based on a partial DYSF amino acid sequence). This kindred also contained individuals with a congenital form of muscular dystrophy (see 254300); none of these individuals carried the DYSF mutation, indicating that it had a different genetic basis.
In a large Canadian aboriginal kindred reported by Weiler et al. (1996), Weiler et al. (1999) found that both patients with limb-girdle muscular dystrophy type 2B (LGMDR2; 253601) and patients with Miyoshi myopathy (MMD1; 254130) were homozygous for a pro791-to-arg (P791R) missense mutation in the DYSF gene. Four additional patients from 2 previously unpublished families also had this mutation. Haplotype analysis suggested a common origin of the mutation in all of the patients. Western blot analysis of muscle in patients with either Miyoshi myopathy or LGMD2B showed a similar abundance of dysferlin staining of 15% and 11%, respectively. Normal tissue sections showed that dysferlin localizes to the sarcolemma, whereas tissue sections from patients with Miyoshi myopathy or limb-girdle muscular dystrophy showed minimal staining that was indistinguishable between the 2 types.
In a large consanguineous pedigree of Yemenite Jewish descent with limb-girdle muscular dystrophy type 2B (LGMDR2; 253601), McNally et al. (2000) identified a homozygous G-to-A change predicted to affect position 5 in the intron following amino acid 1686 (5711 bp) of the dysferlin cDNA sequence. The phenotype associated with this mutation begins in the late second decade and includes an elevated serum creatine kinase. Biopsy samples from these patients demonstrated an inflammatory process, a finding not previously associated with LGMD.
In a large consanguineous Russian family with both limb-girdle muscular dystrophy type 2B (LGMDR2; 253601) and Miyoshi myopathy (MMD1; 254130) reported by Illarioshkin et al. (1996), Illarioshkin et al. (2000) found that all affected individuals were homozygous for a TG-to-AT change at nucleotides 573-574 of the DYSF gene, resulting in a val67-to-asp (V67D) substitution.
In patients with Miyoshi myopathy (MMD1; 254130), Matsumura et al. (1999) identified a 3370G-T transversion in exon 28 of the DYSF gene, resulting in a trp999-to-cys (W999C) substitution. Takahashi et al. (2003) noted that, in general, patients with the W999C mutation tended to have a later age at disease onset (mean, 32 years) and a milder form of the disease.
In a patient with Miyoshi myopathy (MMD1; 254130), Aoki et al. (2001) identified a 3510G-A transition in exon 29 of the DYSF gene, resulting in an arg1046-to-his (R1046H) substitution. Takahashi et al. (2003) noted that patients with the R1046H mutation had a relatively early age at disease onset (mean, 13 years) and a severe form of the disease, with significantly higher serum creatine kinase levels than patients with other mutations in the DYSF gene.
In affected members from 5 families from Sueca, Spain, with a dysferlinopathy, Vilchez et al. (2005) identified a homozygous 6086C-T transition in exon 51 of the DYSF gene, resulting in an arg1905-to-ter (R1905X) substitution. Two families presented with Miyoshi myopathy (MMD1; 254130), 2 presented with distal myopathy with anterior tibial onset (DMAT; 606768), and 1 presented with limb-girdle muscular dystrophy type 2B (LGMDR2; 253601). Although the same mutation resulted in different diagnoses, affected members of each family expressed the same phenotype. The R1905X mutation was not identified in 168 control chromosomes. Haplotype analysis indicated a founder effect. Sueca was founded in 1245 by 17 settlers belonging to the Hospital Order, which received land from King James I of Aragon as a reward for help in reconquering Valencia from the Moors.
In a man with classic limb-girdle muscular dystrophy type 2B (LGMDR2; 253601), Illa et al. (2007) identified compound heterozygosity for 2 mutations in the DYSF gene: an 1873G-T transversion in exon 20 resulting in an asp625-to-tyr (D625Y) substitution and a 5201A-G transition in exon 47 resulting in a glu1734-to-gly (E1734G; 603009.0014) substitution. The patient's 54-year-old sister, who was heterozygous for the D625Y mutation, developed progressive fatigue while walking and difficulty climbing stairs at age 51. She had proximal muscle weakness of the lower limbs, increased serum creatine kinase, and evidence of fatty infiltration of the lower limb muscles on MRI. Although immunostaining and Western blot analysis showed decreased dysferlin levels in the woman's muscle, RT-PCR showed normal levels of DYSF mRNA. The findings indicated that heterozygous DYSF mutation carriers may develop late-onset milder manifestations of the disorder.
For discussion of the glu1734-to-gly (E1734G) mutation in the DYSF gene that was found in compound heterozygous state in a patient with limb-girdle muscular dystrophy type 2B (LGMDR2; 253601) by Illa et al. (2007), see 603009.0013.
In 2 sibs with Miyoshi myopathy (MMD1; 254130), Illa et al. (2007) identified a homozygous 1555G-A transition in exon 18 of the DYSF gene, resulting in a gly519-to-arg (G519R) substitution. Age at onset was 18 and 15 years, respectively, of distal weakness of the lower limbs with progression to proximal muscle involvement and later upper limb involvement. Both were wheelchair-bound in their thirties. The patients' father, who was heterozygous for the G519R mutation, developed calf myalgias and mild progressive difficulties in walking at age 65 years. He had moderately increased serum creatine kinase and decreased dysferlin immunostaining on muscle biopsy, although DYSF mRNA levels were normal. The findings indicated that heterozygous DYSF mutation carriers may develop late-onset milder manifestations of the disorder.
In a woman with mild limb-girdle muscular dystrophy type 2B (LGMDR2; 253601), Sinnreich et al. (2006) identified compound heterozygosity for 2 mutations in the DYSF gene: an A-to-G transition in intron 31, resulting in the in-frame skipping of exon 32, and an indel mutation (603009.0005). The A-to-G mutation was found to lie in the second of 2 putative lariat branch point sequences within the gene. Western blot analysis showed decreased levels of dysferlin, about 10% of normal. The patient's 2 severely affected daughters were homozygous for the indel mutation. Sinnreich et al. (2006) postulated that the mother's milder phenotype resulted from residual protein function due to the splice site mutation.
In 2 sibs with limb-girdle muscular dystrophy type 2B (LGMDR2; 253601), Spuler et al. (2008) identified compound heterozygosity for 2 mutations in the DYSF gene: an 895G-A transition resulting in a gly299-to-arg (G299R) substitution downstream of the second C2 domain, and a 1-bp deletion (855+1delG; 603009.0020) predicted to result in nonsense-mediated decay and lack of protein expression. Skeletal muscle biopsy of both patients showed amyloid fibrils that stained with antibodies against the second C2 domain of dysferlin. Amyloid was located in the sarcolemma of muscle cells, in multiple vessel walls, and in the interstitium. The unaffected father was heterozygous for the G299R mutation and showed no amyloid in skeletal muscle. Spuler et al. (2008) postulated that the mutation destabilized the protein structure and increased the propensity to form amyloid fibrils. An unrelated family with myopathy and a different mutation at this codon (G299W; 603009.0018) also showed amyloidosis in skeletal muscle fibers.
In 2 sibs with Miyoshi myopathy (MMD1; 254130), Spuler et al. (2008) identified a homozygous 895G-T transversion in the DYSF gene, resulting in a gly299-to-trp (G299W) substitution downstream of the second C2 domain. Skeletal muscle biopsy available from 1 patient showed amyloid fibrils that stained with antibodies against the second C2 domain of dysferlin. Amyloid was located in the sarcolemma of muscle cells, in multiple vessel walls, and in the interstitium. Spuler et al. (2008) postulated that the mutation destabilized the protein structure and increased the propensity to form amyloid fibrils. An unrelated family with myopathy and a different mutation at this codon (G299R; 603009.0017) also showed amyloidosis in skeletal muscle fibers.
In an Arab man with limb-girdle muscular dystrophy type 2B (LGMDR2; 253601), Spuler et al. (2008) identified a homozygous A-to-G transition in intron 14 of the DYSF gene, resulting in a splice site mutation near the third C2 domain. Muscle biopsy showed sarcolemmal defects and deposition of amyloid fibrils. Spuler et al. (2008) postulated that the mutation destabilized the protein structure and increased the propensity to form amyloid fibrils.
For discussion of the 1-bp deletion in the DYSF gene (855+1delG) that was found in compound heterozygous state in patients with limb-girdle muscular dystrophy type 2B (LGMDR2; 253601) by Spuler et al. (2008), see 603009.0017.
In 2 Spanish sibs, aged 2 and 5 years, with unusual congenital onset of limb-girdle muscular dystrophy type 2B (LGMDR2; 253601), Paradas et al. (2009) identified a homozygous 1-bp deletion (2776delG) in exon 26 of the DYSF gene, resulting in a frameshift and premature termination. The parents were not consanguineous, but they came from the same small village, and haplotype analysis suggested an ancient consanguineous relationship. Both patients presented in infancy with hypotonia and delayed motor development. They had difficulty walking, running, and climbing stairs, as well as neck muscle weakness. The patients had almost no expression of dysferlin in muscle, whereas clinically unaffected family members who were heterozygous for the mutation had about a 50% reduction in dysferlin expression. Paradas et al. (2009) emphasized the early onset of this disorder in these sibs, and suggested that they have a novel phenotype not previously associated with DYSF mutations.
In 6 unrelated Portuguese male patients with limb-girdle muscular dystrophy type 2B (LGMDR2; 253601), Santos et al. (2010) identified a homozygous 5492G-A transition in the last nucleotide of exon 49 of the DYSF gene. Another Portuguese patient was compound heterozygous for this mutation and another pathogenic mutation in the DYSF gene. The 5492G-A mutation was not found in 240 control alleles. Transcript analysis of patient tissue indicated that the 5492G-A mutation resulted in abnormal splicing, skipping of exon 49, and premature termination. Further studies identified several other residually expressed products of alternative splicing involving exons 50 and 51 in both patients and normal controls, particularly in blood. Haplotype analysis supported a founder effect for the mutation. All 7 patients originated or resided in a confined region of the northern interior part of Portugal. Although most patients had a limb-girdle muscular dystrophy, there was some phenotypic variation: 1 patient presented with distal muscle weakness in the lower limbs, and another had cardiac arrhythmia.
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