title: Revised spectrum of mutations in sarcoglycanopathies.
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.
authors.affiliation: Laboratoire de Biochimie Génétique et Moléculaire, Hôpital Cochin, Paris, France.
authors.forename: Madiha
authors.initials: M
authors.lastname: Trabelsi
authors.forename: Niloufar
authors.initials: N
authors.lastname: Kavian
authors.forename: Fatma
authors.initials: F
authors.lastname: Daoud
authors.forename: Virginie
authors.initials: V
authors.lastname: Commere
authors.forename: Nathalie
authors.initials: N
authors.lastname: Deburgrave
authors.forename: Caroline
authors.initials: C
authors.lastname: Beugnet
authors.forename: Stephane
authors.initials: S
authors.lastname: Llense
authors.forename: Jean Claude
authors.initials: JC
authors.lastname: Barbot
authors.forename: Aurélie
authors.initials: A
authors.lastname: Vasson
authors.forename: Jean Claude
authors.initials: JC
authors.lastname: Kaplan
authors.forename: France
authors.initials: F
authors.lastname: Leturcq
authors.forename: Jamel
authors.initials: J
authors.lastname: Chelly
mesh_terms: D000483:Alleles; D001483:Base Sequence; D015153:Blotting, Western; D020090:Chromosome Segregation / Q000235:genetics; D004252:DNA Mutational Analysis; D005091:Exons / Q000235:genetics; D005260:Female; D005786:Gene Expression Regulation; D005838:Genotype; D006579:Heterozygote; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009136:Muscular Dystrophies / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D020133:Reverse Transcriptase Polymerase Chain Reaction; D049031:Sarcoglycans / Q000235:genetics*; D017384:Sequence Deletion
chemical_list: D049031:Sarcoglycans