title: Mutation spectrum leading to an attenuated phenotype in dystrophinopathies.
abstract: Although Becker muscular dystrophy (BMD; MIM 300376) is mainly caused by gross deletions of the dystrophin gene, the nature of the mutations involved in the remaining cases is of importance because of the milder clinical course of Becker. We have extensively characterized the mRNA changes associated with five novel point mutations giving rise to a Becker phenotype, which confirm that Becker arises largely due to alterations in splicing. In two cases the milder phenotype arises because of exon skipping, leading to an in-frame deletion (c.1603-2A>C and c.4250T>A). In further two cases intronic mutations (c.4519-5C>G and c.961-5925A>C) result in complex splicing changes, but with some residual normal transcripts. The last case, c.10412T>A (p.Leu3471X), results in a truncated transcript missing only part of the COOH terminal of the protein, suggesting that this region is not crucial for dystrophin function. The detection of a low amount of dystrophin in this patient could be attributable to a reduced efficiency of nonsense-mediated decay. The results emphasize that mRNA analysis is important in defining Becker mutations and will be of value in assessing various gene therapy strategies.
authors.affiliation: Laboratoire de Génétique Moleculaire et Chromosomique, CHU de Montpellier, Montpellier, France. tuffery@igh.cnrs.fr
authors.forename: Sylvie
authors.initials: S
authors.lastname: Tuffery-Giraud
authors.forename: Céline
authors.initials: C
authors.lastname: Saquet
authors.forename: Delphine
authors.initials: D
authors.lastname: Thorel
authors.forename: Antoine
authors.initials: A
authors.lastname: Disset
authors.forename: François
authors.initials: F
authors.lastname: Rivier
authors.forename: Sue
authors.initials: S
authors.lastname: Malcolm
authors.forename: Mireille
authors.initials: M
authors.lastname: Claustres
mesh_terms: D000293:Adolescent; D000328:Adult; D001483:Base Sequence; D002648:Child; D018389:Codon, Nonsense; D016189:Dystrophin / Q000235:genetics*; D016368:Frameshift Mutation; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D020388:Muscular Dystrophy, Duchenne / Q000235:genetics* / Q000378:metabolism* / Q000503:physiopathology; D016254:Mutagenesis, Insertional; D009154:Mutation; D010641:Phenotype; D017384:Sequence Deletion
chemical_list: D018389:Codon, Nonsense; D016189:Dystrophin