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Identification of a novel cause of autosomal dominant, adult-onset distal myopathy

Tuesday, October 25, 2011 — Poster Session II

Noon – 2:00 p.m.

Natcher Conference Center




  • MC Malicdan
  • CF Boerkel
  • Y Huang
  • J Kwan
  • C Groden
  • WA Gahl
  • C Toro


Distal myopathies are genetically heterogenous diseases. Associated disease genes are known to encode proteins in the sarcomere (titin, myosin), plasma membrane (dysferlin, caveolin), or cytoskeleton (desmin, myotilin, aB-crystallin, ZASP, filamin C, and nebulin); however, the majority of cases remain undefined. We define a new genetic cause in a two-generation family. Affected individuals have progressive weakness of distal muscles beginning late in the third decade of life without evidence of neuropathy, increased serum CK, respiratory or cardiac symptoms. MRI studies showed fatty replacement of the posterior compartments of the legs. Muscle pathology showed marked variation of fiber size and esoinophilic cytoplasmic inclusions that were devoid of desmin, plasma membrane proteins and oxidative activity, with no rimmed vacuoles. Ultrastructural studies revealed non-membrane bound fibrillary deposits 6-12 microns in diameter in the Z-bands. Whole exome and Sanger sequencing excluded mutations in known genes and identified an intronic splice site mutation causing exon skipping and encoding a frameshift mutation in an unstudied enzyme. Based upon the dominant inheritance and comparable expression of the mutant and wild type mRNAs, the truncated enzyme is an antimorph or neomorph. We present spatiotemporal expression analyses and elucidate the cellular function of the enzyme and the potential disease mechanism.

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