Revised spectrum of mutations in sarcoglycanopathies

Abstract

To define the spectrum of mutations in a-, b-, c-, and d-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 a-and c-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 a-SG was demonstrated in 55.3% of cases (26/47), whereas c-and b-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 a-or c-SG genes, and partial duplications (identified in 5 patients) of exon 1 of b-SG gene. This study highlights the high frequency of exonic deletions of a-and c-SG genes, as well as the presence of a hotspot of duplications affecting exon 1 of the b-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.

Clinical and genetic spectrum in limb-girdle muscular dystrophy type 2E

“…Clinical features in limb-girdle muscular dystrophy 2E Age at onset, y, average 6 SD (range) 9.3 6 8.9 (1.5-40) 4.8 6 2.4 (1.5-9) 16.4 6 11.2 (1.5-40) 5.8 6 2.4 (3)(4)(5)(6)(7)(8)(9) Age at last evaluation, y, average 6 SD (range) 32 6 19.6 (7-67) 28 6 17.9 (13-63) 45 6 15.6 (19-67) 10.4 6 3.4 (7)(8)(9)(10)(11)(12)(13)(14)(15)(16) Deceased patients, n (%) 2 (6) 1 (7) 1 (8) relatively mild LGMD. [14][15][16][17][18][19] LGMD2E is a rare cause of sarcoglycanopathy, with an estimated prevalence of 0.86 3 10 26 cases, 20 and it has generally been considered a severe muscular dystrophy often associated with cardiomyopathy.…”

Combined use of genetic and immunohistochemical analysis is a critical step in differential diagnosis of sarcoglycanopathies

“…Although there were defective expressions of gamma-sarcoglycan protein in all biopsy specimens, the culprit genetic defects could be determined in only nine of them. Most cases had silent homozygous or heterozygous mutations (4)(5)(6)(7) . After this report, we have also diagnosed 19 new patients (3 siblings) with LGMD.…”

“…As a known fact because of the potential variations in residual SGC expressions, genotyoe of sarcoglycanopathies can not be predicted accurately based solely on variable SGC expressions. Therefore, immunoanalysis of skeletal muscle sections for four SGCs must be performed (5)(6)(7) . Besides, concomitant reduction in the levels of dystrophin, and any SGC may play a critical role in the differential diagnosis of dystrophinopathies among sarcoglycan-deficient…”

Lost after translation

“…On ne dispose encore d'aucun traitement pour ces myopathies. C'est la pathologie du gène SGCA (LGMD2D, OMIM 608099) qui est la plus fréquente [14]. Chez la souris, le knock-out du gène Sgca a déjà été effectué (souris Sgca Null/Null ), de même que celui des 3 autres gènes de sarcoglycane, réalisant dans tous les cas un phénotype de dystrophie musculaire sévère [15,16].…”