Revised spectrum of mutations in sarcoglycanopathies

Eur J Hum Genet. 2008 Jul;16(7):793-803. doi: 10.1038/ejhg.2008.9. Epub 2008 Feb 20.

Abstract

To define the spectrum of mutations in alpha-, beta-, gamma-, and delta-sarcoglycan (SG) genes, we analyzed these genes in 69 probands with clinical and biological criteria compatible with the diagnosis of autosomal recessive limb-girdle muscular dystrophy. For 48 patients, muscle biopsies were available and multiplex western blot analysis of muscle proteins showed significant abnormalities of alpha- and gamma-SG. Our diagnostic strategy includes multiplex western blot, sequencing of SG genes, multiplex quantitative-fluorescent PCR and RT-PCR analyses. Mutations were detected in 57 patients and homozygous or compound heterozygous mutations were identified in 75% (36/48) of the patients with abnormal western blot, and in 52% (11/21) of the patients without muscle biopsy. Involvement of alpha-SG was demonstrated in 55.3% of cases (26/47), whereas gamma- and beta-SG were implicated in 25.5% (12/47) and in 17% (8/47) of cases, respectively. Interestingly, we identified 25 novel mutations, and a significant proportion of these mutations correspond to deletions (identified in 14 patients) of complete exon(s) of alpha- or gamma-SG genes, and partial duplications (identified in 5 patients) of exon 1 of beta-SG gene. This study highlights the high frequency of exonic deletions of alpha- and gamma-SG genes, as well as the presence of a hotspot of duplications affecting exon 1 of the beta-SG gene. In addition, protein analysis by multiplex western blot in combination with mutation screening and genotyping results allowed to propose a comprehensive and efficient diagnostic strategy and strongly suggested the implication of additional genes, yet to be identified, in sarcoglycanopathy-like disorders.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Base Sequence
  • Blotting, Western
  • Chromosome Segregation / genetics
  • DNA Mutational Analysis
  • Exons / genetics
  • Female
  • Gene Expression Regulation
  • Genotype
  • Heterozygote
  • Humans
  • Male
  • Molecular Sequence Data
  • Muscular Dystrophies / genetics*
  • Mutation / genetics*
  • Pedigree
  • Reverse Transcriptase Polymerase Chain Reaction
  • Sarcoglycans / genetics*
  • Sequence Deletion

Substances

  • Sarcoglycans