Myotilin is mutated in limb girdle muscular dystrophy 1A

Hum Mol Genet. 2000 Sep 1;9(14):2141-7. doi: 10.1093/hmg/9.14.2141.


We have identified a mutation in the myotilin gene in a large North American family of German descent expressing an autosomal dominant form of limb girdle muscular dystrophy (LGMD1A). We have previously mapped this gene to 5q31. Symptoms of this adult onset disease are progressive weakness of the hip and shoulder girdles, as well as a distinctive dysarthric pattern of speech. Muscle of affected individuals shows degeneration of myofibers, variations in fiber size, fiber splitting, centrally located myonuclei and a large number of autophagic vesicles. Affected muscle also exhibits disorganization and streaming of the Z-line similar to that seen in nemaline myopathy. We have identified a C450T missense mutation in the myotilin gene that is predicted to result in the conversion of residue 57 from threonine to isoleucine. This mutation has not been found in 396 control chromosomes. The mutant allele is transcribed and normal levels of correctly localized myotilin protein are seen in LGMD1A muscle. Myotilin is a sarcomeric protein that binds to alpha-actinin and is localized in the Z-line. The observed missense mutation does not disrupt binding to alpha-actinin.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Actinin / metabolism
  • Adult
  • Alleles
  • Amino Acid Sequence
  • Animals
  • Blotting, Western
  • Cell Nucleus / metabolism
  • Chromatography, High Pressure Liquid
  • Chromosomes, Human, Pair 5
  • Connectin
  • Conserved Sequence
  • Cytoskeletal Proteins
  • Expressed Sequence Tags
  • Female
  • Genes, Dominant
  • Humans
  • Immunohistochemistry
  • Isoleucine / genetics
  • Male
  • Mice
  • Microfilament Proteins
  • Microscopy, Electron
  • Molecular Sequence Data
  • Muscle Proteins / genetics*
  • Muscle Proteins / metabolism
  • Muscle Proteins / ultrastructure
  • Muscular Dystrophies / genetics*
  • Mutation*
  • Mutation, Missense
  • Polymorphism, Single-Stranded Conformational
  • Protein Binding
  • Sequence Analysis, DNA
  • Threonine / genetics
  • Transcription, Genetic
  • Two-Hybrid System Techniques


  • Connectin
  • Cytoskeletal Proteins
  • MYOT protein, human
  • Microfilament Proteins
  • Muscle Proteins
  • Myot protein, mouse
  • Isoleucine
  • Actinin
  • Threonine

Associated data

  • GENBANK/AF230909