Oculopharyngeal muscular dystrophy (OPMD) due to a small duplication in the PABPN1 gene

Abstract

Oculopharyngeal muscular dystrophy (OPMD) is a late onset autosomal dominant muscle disorder. The OPMD-locus has been mapped to chromosome 14q11.2-q13. The polyadenylate binding protein nuclear 1 (PABPN1; PABP2) gene has been identified as the mutated gene. The mutation consists of a short meiotically stable trinucleotide repeat in the first exon of PABPN1 gene. We have investigated Dutch OPMD patients from four unrelated families and identified a new mutation in two of the four families. Instead of a repeat expansion we found a duplication in the first exon of the PABPN1 gene (c.27_28ins12, p.11_12insAAAA). The identification of this new mutation supports the theory of unequal crossing-over as molecular mechanism causing the mutation in the PABPN1 gene responsible for OPMD, and not the slippage model.

Genetic heterogeneity in 30 German patients with oculopharyngeal muscular dystrophy

“…Our data show that (GCG) 7 seems to be very rare in Germany and therefore recessive OPMD is expected to be rare in Germany, too. All (GCN) expansions in OPMD patients reported so far and in our study result in an elongation of a polyalanine tract in the N-terminal domain of PABPN1 [8][9][10][11][12]. Previous works have shown that there is no phenotypic difference between patients with pure GCG expansions and those with additional GCA expansions [8,10,11].All patients of this study also had the typical OPMD phenotype.…”

“…al. et al 2002, 1 family and 1 family of this study[11] (GCG) 6 (GCA) 2 (GCG) 2 (GCA)3 GCG 14 AD van der Sluijs et al 2003, 2 families [12] (GCG) 6 (GCA) 3 GCG (GCA) 3 GCG 14 AD Robinson et al 2005 [13], this study, 4 families Polyalanine repeats other than GCG are underlined. AR autosomal recessive; AD autosomal dominant…”

“…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.…”

“…The gene defect of the disease located in the poly(A) binding protein (PABPN1) gene on chromosome 14q11.2-q13 was identified by Brais et al [1,2]. A (GCG) 6 repeat encoding a polyalanine tract located at the N-terminus of the protein was expanded to (GCG) [7][8][9][10][11][12][13] . The (GCG) 7 allele with only one additional GCG was found to cause recessive oculopharyngeal muscular dystrophy (OPMD) or, in combination with the (GCG) 9 genotype, to lead to a more severe phenotype.…”

“…The mechanism of slippage between short repeats involves DNA polymerase pausing, dissociation of the pausing polymerase from the DNA, separation of the terminal portion of the newly synthesized strand from the template and annealing to another direct repeat [7]. However, additional polyalanine coding triplets (i. e. GCA, GCG) have subsequently been discovered that cannot be readily explained by the replication slippage model [8][9][10][11][12]. In-■ Abstract Oculopharyngeal muscular dystrophy (OPMD) is due to short elongations of a polyalanine tract in the poly(A) binding protein nuclear 1 (PABPN1) gene.…”