G.P.228: Exon 7 deletion in gamma-sarcoglycan gene: evidence of a founder effect in Southern Italy

Abstract

Gamma-sarcoglycanopathy, due to mutations in gamma-sarcoglycan gene, accounts for Limb-Girdle-Muscular Dystrophy 2C (LGMD2C). The disease is frequent in Northern Africa and is prevalently caused by point or missense mutations. Exonic deletions appear to be a rare event, and in cases so far reported they involve intron 2 and exons 2, 6 and 7 of the gene. Intron 2 deletions were reported by C. Bonnemann (1998) in 2 patients, one heterozygous for a 4 base-pair deletion in the splice donor site and a large scale deletion of the second allele, the other homozygous for the same intronic mutation. Deletions of the exon 6 were reported by Nowak (2001) in 2 siblings with a relatively severe LGMD, sharing a compound mutation in exon 3 (Gly69Arg) and the deletion of the exon 6. The homozygous deletion of the exon 7 was firstly described (1998) by our group in two unrelated patients, and subsequently (2005) by Whyte as a compound mutation (c.525delT/del ex.7). In Campania, a region of the Southern Italy, the sarcoglycanopathies are, taken as a whole, the third LGMD by frequency, while LGMD2C represents the first form within this subgroup. We found mutations in gamma-sarcoglycan gene in 20 patients (7 M;13F). Interestingly, 7 of them (35%;1 M;6F), living in the same geographical area at the north of Naples, shared the same homozygous deletion of the exon 7. Compared with those sharing the “del521T” mutation, these patients present a milder phenotype, remain ambulant till their thirties, and free from cardiomyopathy for a longer time. The high occurrence of del7 LGMD2C in our population suggests that this allele is a “private” mutation of this geographical area. We estimate a prevalence of 1:9000 inhabitants, and a carrier frequency of 1:100 in this area, compared with a national prevalence of about 1:18,000. Studies are in progress to assess the haplotypes of the affected individuals and control population, in order to test the presence of a linkage disequilibrium.