Limb girdle muscular dystrophy in unique Manitoba populations
Limb girdle muscular dystrophy (LGMD) is a clinically and genetically heterogeneous group of disorders known to be caused by mutations at more than 12 loci. The objective of this work was to identify the genetic basis of the LGMD in two inbred populations in Manitoba (aboriginal and Hutterite). In the aboriginal population, 15 patients from two widely separated communities were identified with either proximal LGMD or distal myopathy. Linkage analysis of known loci in these families excluded all but 'LGMD2B'. Haplotype analysis of the 'LGMD2B' locus on chromosome 2p13 revealed that individuals affected with either LGMD or distal myopathy were homozygous for a single haplotype, suggesting that they would also be homozygous for the disease-causing mutation. After dysferlin was identified as the gene responsible for LGMD2B/MM, mutation analysis of the 'DYSF' gene confirmed this hypothesis, leading us to postulate that additional factors, either genetic or environmental, must be causing the differences in the phenotype. Furthermore, the identification of a single disease-causing mutation and surrounding haplotype in the two distinct aboriginal communities suggests that these apparently unrelated communities share common ancestry. In the Hutterite population, 44 patients were identified with LGMD. Thirty-three of these patients were excluded from linkage to all known LGMD loci. A genome scan using a DNA pooling strategy resulted in the identification of a new locus for LGMD on chromosome 9q31-q33 which received the gene symbol ' LGMD2H'. Additional linkage and haplotype analysis of more than 100 individuals using 25 microsatellite markers refined the interval to an area flanked by 'D9S1126' and 'D9S737'. Genetic recombination analysis and physical mapping of the candidate interval by YAC and genomic sequence contig analysis has allowed us to order the chromosome 9q32 loci and estimate the size of the candidate interval to be less than 1 Mb. Three candidate genes located within this interval ('PAPPA, ASTN2' and 'HT2A') are being evaluated for disease-causing mutations in LGMD2H patients. Eleven of the 44 Hutterite patients did not show linkage to the ' LGMD2H' locus on chromosome 9q3. These results indicate that there are at least two loci causing LGMD among the Hutterites.