Unequal Crossing-over in Unique PABP2 Mutations in Japanese Patients

Abstract

The mutated alleles identified in our Japanese patients with OPMD were most likely due to duplications of (GCG)(3)GCA and (GCG)(2)(GCA)(3) but not simple expansions of the GCG repeats. Therefore, unequal crossing-over of 2 PABP2 alleles, rather than DNA slippage, is probably the causative mechanism of OPMD mutations. All mutations that have been reported in patients with OPMD so far can be explained with the mechanism of unequal crossing-over. On the other hand, comparison of the clinical features of our patients with those of other patients in previous reports suggests that specific clinical features cannot be attributed to the length of the polyalanine tract per se.

Oculopharyngeal muscular dystrophy: a late-onset polyalanine disease

“…Although slippage during replication was proposed in the first paper describing the PABPN1 mutations in OPMD, two reports suggest that unequal recombinations may be responsible for some, if not all, OPMD mutations (Brais et al, 1998b;Nakamoto et al, 2002). This would correspond to what is believed to be the mutation mechanism in the other polyalanine diseases (Warren, 1997).…”

“…In populations with founder effects, such as in French Canadians or Bukhara Jews, most families will share the same historical mutation, which will only rarely have changed size (Brais et al, 1998b;Blumen et al, 2000). Two studies have raised the possibility that some of the OPMD mutations are not due to expansions of the GCG stretch but are secondary to insertion of nonidentical polyalanine coding triplets (Scacheri et al, 1999;Nakamoto et al, 2002). It was suggested that both types of OPMD mutations are caused by unequal crossing-over (Nakamoto et al, 2002).…”

“…Two studies have raised the possibility that some of the OPMD mutations are not due to expansions of the GCG stretch but are secondary to insertion of nonidentical polyalanine coding triplets (Scacheri et al, 1999;Nakamoto et al, 2002). It was suggested that both types of OPMD mutations are caused by unequal crossing-over (Nakamoto et al, 2002). This has been considered to be the major cause of polyalanine expansion mutations in other polyalanine diseases (Warren, 1997).…”

The contribution of <i>cis</i>-elements to disease-associated repeat instability: clinical and experimental evidence

“…Disease development at these loci may relate more to the protein context of the repeat. While some of these loci do not display somatic instability (Nakamoto et al, 2002), disease progression does occur at these loci at repeat lengths far below the stability threshold of most disease-associated TNRs. The small changes in repeat number at these loci causing disease development are compatible with replicative slippage as the underlying mutation mechanism.…”

Neurological diseases and RNA-directed gene regulation: prospects for new diagnostics and therapy

“…Indeed, neuronal intranuclear inclusions and/or cytoplasmic aggregates containing mutant proteins have been demonstrated in transgenic mice bearing mutant HD genes, as well as in autopsied brains from patients with CAG-repeat diseases [9,10]. Recently, the repertoire of exonic mutations has been enlargeda GCG-repeat expansion coding for the polyalanine string has been detected in the gene coding for a poly(A)-binding protein linked to the oculopharyngeal muscular atrophy (TABLE 1) [11].…”