Revised spectrum of mutations in sarcoglycanopathies.
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.
Trabelsi
Madiha
M
Laboratoire de Biochimie Génétique et Moléculaire, Hôpital Cochin, Paris, France.
Kavian
Niloufar
N
Daoud
Fatma
F
Commere
Virginie
V
Deburgrave
Nathalie
N
Beugnet
Caroline
C
Llense
Stephane
S
Barbot
Jean Claude
JC
Vasson
Aurélie
A
Kaplan
Jean Claude
JC
Leturcq
France
F
Chelly
Jamel
J
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
D049031:Sarcoglycans