Genetic heterogeneity in 30 German patients with oculopharyngeal muscular dystrophy

Oculopharyngeal muscular dystrophy (OPMD) is due to short elongations of a polyalanine tract in the poly(A) binding protein nuclear 1 (PABPN1) gene. Originally GCG expansions in which (GCG)(6) is extended to (GCG)(7-13) were found. Subsequently five further genotypes with additional GCA- and GCG-trinucleotides were identified in single OPMD patients. This indicated larger genetic heterogeneity and showed that unequal crossing-over and not replication slippage must be the underlying mechanism of elongation.We performed sequencing of the PABPN1 gene in 30 German OPDM index patients to determine the exact genotype. The original GCG expansion ranging from (GCG)(8) to (GCG)(11) was found in 22 patients. In 8 patients, however, three different elongated alleles other than classical (GCG)(7-13) were observed. Two of these genotypes had already been identified in Japanese patients. One genotype was recently identified showing (GCG)(6) followed by inserted (GCA)(3)GCG in four unrelated patients. This study further supports the theory of unequal crossing over as the molecular mechanism leading to elongation. It shows that other genotypes than classical (GCG)(7-13) are rather common in German OPMD patients. The data imply that there is no single founder effect in German OPMD patients.