DYSF – Miyoshi Myopathy

Miyoshi myopathy (MM) is an adult-onset, autosomal recessive distal muscular dystrophy characterized by weakness and atrophy of the posterior calf muscles and markedly elevated serum creatine kinase levels. The DYSF gene (HGNC:3097) on chromosome 2p13 encodes dysferlin, a membrane-associated protein involved in sarcolemmal repair. MM and limb-girdle muscular dystrophy type 2B (LGMD2B) represent allelic dysferlinopathies with overlapping histopathology and immunohistochemical features. The MM locus was refined to a 2 Mb interval by mapping studies, and initial gene discovery described nine mutations in nine families, five predicted to abolish dysferlin expression (PMID:9731526). Subsequent case series have confirmed a consistent recessive inheritance pattern. Phenotypic variance in individuals with identical mutations suggests additional genetic or epigenetic modifiers.

Genetic evidence for DYSF in MM includes biallelic pathogenic variants in over 134 unrelated patients, with two alleles identified in 89 cases and one allele in 30 additional cases (PMID:18853459). Deep intronic mutations that introduce pseudoexons have been identified in 23 patients from 17 families and corrected in vitro by antisense oligonucleotides (PMID:31019989). A single founder mutation (c.5830C>T) in the Spanish population accounted for multiple phenotypes in eight patients homozygous within one region (PMID:16087766). In a multigenerational Dagestan kindred, 12 affected members were homozygous for the TG573/574AT (p.Val68Asp) variant, underscoring segregation across three generations (PMID:28337173). Case reports, such as a Korean MM patient harboring homozygous c.1261G>A (p.Glu421Lys), further demonstrate pathogenicity and diagnosis confirmation by immunohistochemistry and sequencing (PMID:15515206).

The DYSF variant spectrum spans missense (e.g., c.1261G>A (p.Glu421Lys)), nonsense (~50), frameshift, splice-site, and deep intronic mutations. Recurrent and founder alleles include p.Gln832Ter (10/46 alleles; Korean population) and c.663+1G>C, accounting for approximately one-third of Korean mutations (PMID:22297152). Population allele frequencies are low, consistent with recessive inheritance; carrier prevalence ranges from 1:1 300 to 1:200 000. Genotype–phenotype correlations are limited, with identical variants producing LGMD2B or MM within and between families.

Functional studies confirm dysferlin’s role in membrane repair: Western blot and immunohistochemistry analysis of unclassified myopathy biopsies identified dysferlin deficiency in 26 cases, with absent or severely reduced protein in muscle (PMID:11245721). Antisense oligonucleotides targeting pseudoexon 44.1 corrected aberrant splicing and restored full-length DYSF expression in myogenic cells (PMID:31019989). Recombinant human MG53 protein enhances membrane integrity in dysferlin-deficient mouse muscle fibers, indicating adjunctive therapeutic potential (PMID:28750735). Cellular and animal models replicate key pathological features and rescue experiments further strengthen mechanistic understanding.

Some studies report symptomatic heterozygous carriers with reduced dysferlin levels, suggesting possible dominant-negative effects or incomplete penetrance (PMID:17287450). Routine genomic screening may miss noncoding or deep intronic alleles, thus necessitating combined genetic and protein analyses. However, no refuting data challenge the autosomal recessive model or the fundamental role of dysferlin in MM.

Collectively, genetic evidence from multigenerational families, cohort studies, and case reports, alongside robust functional concordance across cellular and animal models, establishes DYSF as definitively associated with Miyoshi myopathy. The autosomal recessive inheritance, broad variant spectrum, and reliable diagnostic biomarkers (e.g., absent dysferlin staining) support inclusion of DYSF testing in early diagnostic workflows. Functional assays, including membrane repair and splicing correction, underscore promising therapeutic avenues. Further research may elucidate modifier genes influencing clinical variability. Key take-home: Combined DYSF sequencing and dysferlin protein analysis enable precise diagnosis and stratification for emerging therapies in Miyoshi myopathy.

References

• Nature genetics • 1998 • Dysferlin, a novel skeletal muscle gene, is mutated in Miyoshi myopathy and limb girdle muscular dystrophy. PMID:9731526
• Human mutation • 2009 • Analysis of the DYSF mutational spectrum in a large cohort of patients. PMID:18853459
• Annals of clinical and translational neurology • 2019 • Correction of pseudoexon splicing caused by a novel intronic dysferlin mutation. PMID:31019989
• Archives of neurology • 2005 • Identification of a novel founder mutation in the DYSF gene causing clinical variability in the Spanish population. PMID:16087766
• Frontiers in neurology • 2017 • Twenty-Year Clinical Progression of Dysferlinopathy in Patients from Dagestan. PMID:28337173
• Yonsei medical journal • 2004 • Identification of a dysferlin gene mutation in a Korean case with Miyoshi myopathy. PMID:15515206
• Neuromuscular disorders : NMD • 2012 • Two common mutations (p.Gln832X and c.663+1G>C) account for about a third of the DYSF mutations in Korean patients with dysferlinopathy. PMID:22297152
• Neurology • 2001 • Calpain-3 and dysferlin protein screening in patients with limb-girdle dystrophy and myopathy. PMID:11245721
• Molecular therapy : the journal of the American Society of Gene Therapy • 2017 • Treatment with Recombinant Human MG53 Protein Increases Membrane Integrity in a Mouse Model of Limb Girdle Muscular Dystrophy 2B. PMID:28750735
• Neurology • 2007 • Symptomatic dysferlin gene mutation carriers: characterization of two cases. PMID:17287450

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