Abstract
To define the spectrum of mutations in α-, β-, γ-, and δ-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 α- and γ-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 α-SG was demonstrated in 55.3% of cases (26/47), whereas γ- and β-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 α- or γ-SG genes, and partial duplications (identified in 5 patients) of exon 1 of β-SG gene. This study highlights the high frequency of exonic deletions of α- and γ-SG genes, as well as the presence of a hotspot of duplications affecting exon 1 of the β-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.
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Acknowledgements
We express our thanks for the patients and families for their participation in the study, and the physicians for referring patients to our diagnostic laboratory. We also thank all members of the laboratoire de Biochimie Génétique et Moléculaire, and the Cell Bank of Cochin Hospital for their technical help. This study was supported by grants from AP-HP, INSERM, FRM and AFM.
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Supplementary Information accompanies the paper on European Journal of Human Genetics website (http://www.nature.com/ejhg)
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Trabelsi, M., Kavian, N., Daoud, F. et al. Revised spectrum of mutations in sarcoglycanopathies. Eur J Hum Genet 16, 793–803 (2008). https://doi.org/10.1038/ejhg.2008.9
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DOI: https://doi.org/10.1038/ejhg.2008.9
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