DYSF – Autosomal Recessive Limb-Girdle Muscular Dystrophy

DYSF encodes the transmembrane protein dysferlin, a key mediator of Ca2+-dependent sarcolemmal membrane repair in skeletal muscle. Loss-of-function variants in DYSF cause autosomal recessive limb-girdle muscular dystrophy type 2B (LGMDR2) and Miyoshi myopathy, characterized by progressive weakness, elevated serum creatine kinase, and eventual loss of ambulation (HP:0002505) and frequent cardiac involvement (HP:0001627).

In a Dutch multi-center cohort of 244 AR-LGMD and MMD patients, 25 individuals (10%) harbored biallelic DYSF mutations, including 33 novel alleles detected by sequencing and MLPA, establishing DYSF as a recurrent cause of AR-LGMD (25 probands) ([PMID:30919934]). Variants spanned nonsense, frameshift, splice, and missense classes: for example, c.3762del (p.Asp1255fs) in two unrelated patients ([PMID:30919934]).

Segregation data are limited but include a Spanish founder mutation c.5830C>T (p.Arg1944Ter) in homozygosity across 5 families with consistent phenotypes ([PMID:16087766]). The deep intronic variant c.5003+1249G>T creates a pseudoexon rescued by antisense oligonucleotides in vitro ([PMID:25493284]), underscoring the allelic heterogeneity and diagnostic challenges.

Functional studies demonstrate absent or severely reduced dysferlin by Western blot and immunohistochemistry in 26% of unclassified dystrophy biopsies ([PMID:11245721]). Splice-variant Δ17 influences isoform distribution during myogenesis ([PMID:15318348]), while caveolin-3 mutations disrupt dysferlin trafficking to the plasma membrane ([PMID:16319126]).

Rescue assays confirm pathogenic mechanism: ataluren-mediated read-through of R1905X restores membrane blebbing in patient myotubes ([PMID:20558759]), and recombinant MG53 protein enhances membrane integrity in dysferlin-deficient mice ([PMID:28750735]). These concordant models support haploinsufficiency as the disease mechanism.

Integration of 25 genetically confirmed AR-LGMD2B probands, recurrent and deep intronic alleles, and multiple rescue models yields strong clinical validity. Comprehensive DYSF testing facilitates diagnosis, carrier detection, and eligibility for emerging therapies. Key take-home: DYSF variant screening and functional assays are critical for accurate diagnosis and therapeutic stratification in AR-LGMD.

References

• Clinical Genetics • 2019 • Autosomal recessive limb-girdle and Miyoshi muscular dystrophies in the Netherlands: The clinical and molecular spectrum of 244 patients. PMID:30919934
• Neurology • 2001 • Calpain-3 and dysferlin protein screening in patients with limb-girdle dystrophy and myopathy. PMID:11245721
• Archives of Neurology • 2005 • Identification of a novel founder mutation in the DYSF gene causing clinical variability in the Spanish population. PMID:16087766
• Muscle & Nerve • 2004 • Developmental and tissue-specific regulation of a novel dysferlin isoform. PMID:15318348
• Human Molecular Genetics • 2006 • Aberrant dysferlin trafficking in cells lacking caveolin or expressing dystrophy mutants of caveolin-3. PMID:16319126
• Journal of Applied Physiology • 2010 • Membrane blebbing as an assessment of functional rescue of dysferlin-deficient human myotubes via nonsense suppression. PMID:20558759
• Annals of Clinical and Translational Neurology • 2014 • A novel dysferlin mutant pseudoexon bypassed with antisense oligonucleotides. PMID:25493284
• Molecular Therapy • 2017 • Treatment with Recombinant Human MG53 Protein Increases Membrane Integrity in a Mouse Model of Limb Girdle Muscular Dystrophy 2B. PMID:28750735

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