Genetic heterogeneity in 30 German patients with oculopharyngeal muscular dystrophy

Abstract

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.

Unique PABPN1 gene mutation in a large Bulgarian family with OPMD

“…Our findings and previous studies suggest that neither the type of trinucleotide repeats, nor the size of the expansions sufficiently explain the observed phenotypic variability in OPMD [6,7]. Additional genetic factors are likely to modify the OPMD phenotype.…”

“…In contrast to other populations, where the majority of OPMD patients carry classical GCG repeat expansions, our single Bulgarian family demonstrated a non-GCG elongation, further supporting the genetic heterogeneity and probably the existence of multiple founders of OPMD [3,4,6,9].…”

“…Similar to the other reported OPMD mutations, additional (GCA) 3 repeats can be the result of a duplication of the wildtype (GCA) 3 due to unequal crossingover of two PABPN1 alleles [6,7,[9][10][11].…”

“…However, Unique PABPN1 gene mutation in a large Bulgarian family with OPMD Sirs: Oculopharyngeal muscular dystrophy (OPMD) is a late onset muscle disorder characterized by progressive ptosis, dysphagia and proximal limb weakness in some patients [12]. It is caused by short GCG expansions or different combinations of GCA and GCG trinucleotides in the first exon of the poly(A) binding-protein nuclear 1 (PABPN1) gene [2,3,6,7,[9][10][11]. Patients with OPMD have been reported world-wide, but cases from Bulgaria were not reported so far.…”

“…The part of exon 1 of the PABPN1 gene containing the GCG/GCA elongation was sequenced as described [6].…”