DYSF – Dysferlin Deficiency (Qualitative or Quantitative Defects of Dysferlin)

Dysferlinopathy is an autosomal recessive muscle disorder caused by biallelic mutations in the DYSF gene. Affected individuals typically present in adolescence or early adulthood with limb-girdle muscular dystrophy type R2 (LGMDR2) or distal Miyoshi myopathy, although phenotypes range from asymptomatic hyperCKemia to congenital onset and rigid spine syndrome. Serum creatine kinase (CK) levels are markedly elevated, sometimes exceeding 900,000 IU/L in rhabdomyolysis episodes. Muscle imaging shows selective fatty replacement, most pronounced in posterior thigh, calf, and paraspinal muscles, with a myogenic pattern on electromyography.

Extensive genetic studies have identified over 400 distinct DYSF variants in more than 245 unrelated patients ([PMID:34559919]). These include missense (≈40%), loss-of-function (30%), splice-site (18%), intronic/deep-intronic, and structural rearrangements. Founder variants have been documented (e.g., c.200_201delinsAT, p.Val67Asp in Dagestan at 14% allele frequency ([PMID:37553796])) and common splice-site mutations (c.663+1G>C in Koreans, accounting for 34.8% of alleles). The case report of c.5392G>A (p.Gly1798Ser) in a patient misdiagnosed with inflammatory myopathy underscores the diagnostic yield of targeted gene panels and segregation analysis in confirming compound heterozygotes ([PMID:29799141]).

Segregation analysis in multiplex families supports autosomal recessive inheritance, with co-segregation of biallelic variants in 23 families studied across diverse populations ([PMID:17070050]). Monoallelic carriers are typically asymptomatic, although rare heterozygotes may exhibit hyperCKemia. Rigid spine syndrome and contractures are uncommon but documented in adolescence-onset Miyoshi myopathy ([PMID:38365661]).

Functional assays demonstrate concordant pathogenicity: cDNA from peripheral blood monocytes enables reliable diagnostic testing and mutation screening ([PMID:17070050]). In vivo studies using a naturally occurring “minidysferlin” deletion validated by rAAV-mediated gene transfer restore sarcolemmal repair in Dysf-null mice ([PMID:20861509]). Antisense oligonucleotides targeting a deep-intronic pseudoexon (PE44.1) successfully restore normal splicing and dysferlin expression in patient cells ([PMID:25493284]). Membrane-blebbing assays of patient myotubes show functional rescue with read-through compounds (ataluren) for nonsense mutations such as c.5830C>T (p.Arg1944Ter) ([PMID:20558759]), and recombinant MG53 protein improves sarcolemmal integrity independent of dysferlin ([PMID:28750735]). Targeted RNA-Seq increases diagnostic yield by reclassifying VUS and identifying novel pathogenic variants ([PMID:36983702]).

Collectively, these genetic and functional data fulfill ClinGen criteria for a Definitive gene-disease relationship: numerous unrelated probands, robust segregation in multiple families, and concordant functional evidence in cellular and animal models.

Key Take-home: DYSF sequencing combined with monocyte mRNA analysis ensures accurate dysferlinopathy diagnosis, informs carrier screening in high-risk populations, and underpins emerging RNA- and gene-based therapeutic strategies.

References

• Human Mutation • 2021 • Molecular landscape of DYSF mutations in dysferlinopathy: From a Chinese multicenter analysis to a worldwide perspective PMID:34559919
• Neuromuscular Disorders • 2007 • Dysferlin expression in monocytes: a source of mRNA for mutation analysis PMID:17070050
• Neuropathology • 2018 • A novel mutation in the DYSF gene in a patient with a presumed inflammatory myopathy PMID:29799141
• Molecular Genetics & Genomic Medicine • 2023 • Genetic screening of an endemic mutation in the DYSF gene in an isolated, mountainous population in the Republic of Dagestan PMID:37553796
• Science Translational Medicine • 2010 • A naturally occurring human minidysferlin protein repairs sarcolemmal lesions in a mouse model of dysferlinopathy PMID:20861509
• Annals of Clinical and Translational Neurology • 2014 • A novel dysferlin mutant pseudoexon bypassed with antisense oligonucleotides. PMID:25493284
• Journal of Applied Physiology (Bethesda, Md.: 1985) • 2010 • Membrane blebbing as an assessment of functional rescue of dysferlin-deficient human myotubes via nonsense suppression. PMID:20558759
• Molecular Therapy • 2017 • Treatment with Recombinant Human MG53 Protein Increases Membrane Integrity in a Mouse Model of Limb Girdle Muscular Dystrophy 2B. PMID:28750735
• Journal of Personalized Medicine • 2023 • Utilization of Targeted RNA-Seq for the Resolution of Variant Pathogenicity and Enhancement of Diagnostic Yield in Dysferlinopathy. PMID:36983702

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