DYSF – Limb-girdle Muscular Dystrophy Type 2B (LGMD2B)

Limb-girdle muscular dystrophy type 2B (LGMD2B) is an autosomal recessive disorder characterized by progressive proximal muscle weakness and elevated serum creatine kinase. Biallelic pathogenic variants in DYSF (HGNC:3097) disrupt dysferlin-mediated sarcolemmal repair, leading to muscle fiber degeneration and dystrophic histology.

Clinical Validity

The DYSF–LGMD2B association is classified as Strong based on >200 unrelated probands, including 134 patients in a large cohort (PMID:18853459) and 34 in another series (PMID:16010686). Segregation of variants in 17 families supports recessive inheritance (PMID:31019989). Functional concordance across multiple model systems further reinforces causality.

Genetic Evidence

LGMD2B follows an autosomal recessive inheritance pattern with affected individuals harboring homozygous or compound heterozygous LoF and missense DYSF variants. Segregation analysis identified 17 families with a deep intronic founder variant causing pseudoexon inclusion (PMID:31019989). Over 416 pathogenic alleles have been described, including nonsense, frameshift, splice-site, and missense changes. A recurrent stop-gain, c.268C>T (p.Arg90Ter) (PMID:23641709), exemplifies the LoF spectrum. Founder mutations such as p.Gln832Ter in Korean patients further highlight population-specific alleles.

Functional Evidence

Dysferlin deficiency is confirmed by absent or reduced sarcolemmal staining and immunoblot in patient muscle biopsies and blood monocytes. Membrane repair assays demonstrate impaired blebbing in dysferlin-deficient myotubes and rescue upon ataluren treatment of R1905X nonsense alleles (PMID:20558759). Recombinant human MG53 restores membrane integrity in dysferlin-null mice, indicating therapeutic potential (PMID:28750735). Domain-specific structural studies reveal that pathogenic variants disrupt C2 and DysF domains, impairing protein folding and trafficking (PMID:24438169).

Mechanism and Interpretation

Loss of functional dysferlin leads to defective membrane resealing following microinjury, triggering muscle fiber necrosis and chronic degeneration. Both in vitro and in vivo rescue experiments establish the critical role of dysferlin in sarcolemmal repair and underscore the potential for exon-skipping and protein replacement therapies. No compelling conflicting evidence has been reported.

Key Take-home: Biallelic DYSF variants cause LGMD2B through loss of membrane repair, supporting genetic testing for accurate diagnosis and guiding emerging therapeutic strategies.

References

• Identical mutation in patients with limb girdle muscular dystrophy type 2B or Miyoshi myopathy suggests a role for modifier gene(s). Human molecular genetics | 1999 PMID:10196377
• Dysferlin mutations in LGMD2B, Miyoshi myopathy, and atypical dysferlinopathies. Human mutation | 2005 PMID:16010686
• Analysis of the DYSF mutational spectrum in a large cohort of patients. Human mutation | 2009 PMID:18853459
• Correction of pseudoexon splicing caused by a novel intronic dysferlin mutation. Annals of clinical and translational neurology | 2019 PMID:31019989
• Membrane blebbing as an assessment of functional rescue of dysferlin-deficient human myotubes via nonsense suppression. Journal of applied physiology | 2010 PMID:20558759
• Treatment with Recombinant Human MG53 Protein Increases Membrane Integrity in a Mouse Model of Limb Girdle Muscular Dystrophy 2B. Molecular therapy | 2017 PMID:28750735

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