A Common Haplotype Associated with the Basque 2362AG → TCATCT Mutation in the Muscular Calpain-3 Gene

Limb-girdle muscular dystrophy type 2A (LGMD2A) is caused by any of over 150 mutations in the calpain-3 (CAPN3) gene. Of those, 2362AG → TCATCT is particularly prevalent in Basque patients, and this mutation was hypothesized to have arisen in the Basque Country. To explore the natural history of this mutation, we genotyped 65 Basque and non-Basque patients with LGMD2A who carry the 2362AG → TCATCT mutation for four microsatellites within or flanking the gene. A particular haplotype was found in three-fourths of the patients and was assumed to be ancestral. From the average number of recombinations and mutations accumulated from this ancestral haplotype, the age of the 2362AG → TCATCT mutation was estimated to be 50 generations (i.e., 1,250 years), which is more recent than the Paleolithic Basque heritage. The subsequent spread of the 2362AG → TCATCT mutation can be related to gene flow out of the Basque Country, even across a cultural border.