DMD Trp3X nonsense mutation associated with a founder effect in North American families with mild Becker muscular dystrophy

Kevin M. Flanigan, Diane M. Dunn, Andrew von Niederhausern, Michael T. Howard, Jerry Mendell, Anne Connolly, Carol Saunders, Ann Modrcin, Majed Dasouki, Giacomo P. Comi, Roberto Del Bo, Angela Pickart, Richard Jacobson, Richard Finkel, Livija Medne, Robert B. Weiss

Research output: Contribution to journalArticlepeer-review

Abstract

A recurrent exon 1 nonsense mutation in the DMD gene, p.Trp3X (c.9G > A), was first ascertained in a proband with no symptoms until age 20 and who walked until the age of 62. Six other unrelated kindreds carrying a p.Trp3X mutation were subsequently ascertained, five from North America and one from Italy. In six of the seven kindreds, the proband presented in childhood incidental to elevated creatine kinase levels detected in the context of other illnesses, or in the setting of cramps with or without rhabdomyolysis. Genetic analysis by high density SNP genotyping demonstrates that the six North American families share a 3.7 Mbp haplotype surrounding the p.Trp3X allele, signifying that this is a founder mutation in these individuals. The size of the founder haplotype and the structure of shared genome-wide segments suggests that the minimal age of this mutation is >6 generations. The discovery of the first DMD founder mutation, associated with a mild Becker phenotype, suggests that the prevalence of hypomorphic dystrophin mutations should be re-examined with the use of improved genomic analysis.

Original languageEnglish
Pages (from-to)743-748
Number of pages6
JournalNeuromuscular Disorders
Volume19
Issue number11
DOIs
Publication statusPublished - Nov 2009

Keywords

  • Becker muscular dystrophy
  • DMD
  • Duchenne muscular dystrophy
  • Founder allele

ASJC Scopus subject areas

  • Clinical Neurology
  • Pediatrics, Perinatology, and Child Health
  • Genetics(clinical)
  • Neurology

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