Prevalence and ancestral origin of the c.1987delC GAA gene mutation causing Pompe disease in Central Mexico

Pompe Disease (PD) is a rare autosomal recessive disorder caused by lysosomal enzyme acid-alpha-glucosidase (GAA) deficiency, which leads to lysosomal glycogen accumulation, swelling, cellular damage and dysfunction of cardiac, respiratory and muscular tissue. In Mexico, < 100 PD cases have been diagnosed. Recently, three apparently unrelated classic infantile PD cases coming from three different isolated communities of Central Mexico were diagnosed at the same hospital in the State of San Luis Potosi, and were found to be homozygous for a novel frameshift GAA gene mutation (c.1987delC). The purpose of the study was to determine mutation carrier frequencies in these localities, to alert the authorities on the high risk of PD in this region, to gain insight on the structural effects of the mutation by protein modeling, and to disclose the ancestral origin of the mutation. Quantitative PCR analyses showed that 24/307 (7.8%) subjects from two of the communities were heterozygous for the mutation. A genetic counseling campaign and newborn screening were organized with the help of local authorities. Tridimensional modeling predicted the mutant c.1987delC the second of the 3 GAA domains would be improperly folded and the third domain missing. Global ancestry analysis of six individuals from these communities (5 mutation carriers and 1 non-carrier) showed that > 95% of their genetic component was of Native Mexican origin, while < 4% was of European origin. The GAA mutation was found to lie within a segment of Native Mexican ancestry, probably Mayan-Zapotec.