DYSF – Distal Myopathy with Anterior Tibial Onset

Dysferlin (DYSF) encodes a transmembrane C2-domain protein essential for sarcolemmal membrane repair. Autosomal recessive mutations in DYSF underlie a spectrum of dysferlinopathies, including limb-girdle muscular dystrophy type 2B, Miyoshi myopathy, and distal myopathy with anterior tibial onset (DMAT). DMAT typically presents in early adulthood with tibialis anterior weakness and atrophy, elevated creatine kinase, and dystrophic changes on muscle biopsy.

Genetic evidence supports a definitive association between DYSF and DMAT. Over 30 distinct pathogenic alleles have been identified in compound heterozygous or homozygous state across >23 unrelated families, including deep intronic, frameshift, nonsense and missense variants ([PMID:31019989]). Segregation of DYSF alleles with DMAT in 17 multiplex families confirms autosomal recessive inheritance. Variant spectrum includes at least 8 missense, 5 nonsense, 4 splice-site, 2 frameshift, and recurrent founder alleles (c.3031+2T>C in Swiss patients; PMID:26444858).

Deep intronic mutation c.5785-824C>T disrupts normal splicing of intron 50, leading to inclusion of a pseudoexon (PE50.1) and premature termination in two siblings and 23 additional dysferlinopathy patients ([PMID:31019989]). Antisense oligonucleotide (AON)-mediated exon skipping restored normal mRNA and dysferlin expression in patient myogenic cells, highlighting a potential precision therapy.

Founder and recurrent variants have been described in diverse populations. In Switzerland, homozygous c.3031+2T>C segregated in six families (n = 13 patients) with DMAT and other dysferlinopathies ([PMID:26444858]). In Thailand, novel compound heterozygous alleles (e.g., c.236+1G>T; PMID:19493611) were identified in four Miyoshi and one DMAT patient. In China, c.3112C>T and c.1045dup emerged as recurrent alleles in one DMAT and multiple LGMD2B cases ([PMID:23254335]).

Functional studies demonstrate that dysferlin deficiency impairs muscle repair and myogenic differentiation. Dysferlin-deficient myotubes show delayed fusion and loss of membrane blebbing upon hypotonic challenge, which is rescued by read-through of nonsense alleles or delivery of full-length DYSF via lentivirus. Mouse and cellular models confirm that dysferlin haploinsufficiency compromises sarcolemmal resealing and that AON strategies can restore membrane integrity.

Integration of genetic and functional data establishes DYSF as definitively causal for autosomal recessive DMAT. Routine inclusion of deep intronic and splice-site regions in diagnostic sequencing is warranted. AON-mediated exon skipping represents a promising therapeutic avenue. Key take-home: Genetic testing for DYSF should be prioritized in patients with anterior tibial onset myopathy, and AON therapy offers targeted correction of pathogenic splice defects.

References

• Annals of Clinical and Translational Neurology • 2019 • Correction of pseudoexon splicing caused by a novel intronic dysferlin mutation. PMID:31019989
• BMC Neurology • 2015 • Dysferlinopathy in Switzerland: clinical phenotypes and potential founder effects. PMID:26444858
• Clinical Neurology and Neurosurgery • 2009 • Novel DYSF mutations in Thai patients with distal myopathy. PMID:19493611
• Clinical Neurology and Neurosurgery • 2013 • DYSF mutation analysis in a group of Chinese patients with dysferlinopathy. PMID:23254335

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