Oculopharyngeal muscular dystrophy: a late-onset polyalanine disease

Abstract

Oculopharyngeal muscular dystrophy (OPMD) is a muscle disease of late onset associated with progressive ptosis of the eyelids, dysphagia, and unique tubulofilamentous intranuclear inclusions (INIs). OPMD is usually transmitted as an autosomal dominant trait (OMIM 164300). A rarer allelic autosomal recessive form has also been observed (OMIM 257950). Both forms are caused by short (GCG)_8–13 expansions in the polyadenylate-binding protein nuclear 1 gene (PABPN1) located on chromosome 14q11.1. The mutations cause the lengthening of an N-terminal polyalanine domain. Both slippage and unequal recombination have been proposed as the mutation mechanisms. The size of the mutation has not yet been conclusively shown to inversely correlate with the severity of the phenotype. Mutated PABPN1 proteins have been shown to be constituents of the INIs. The INIs also contain ubiquitin, proteasome subunits, HSP 40, HSP 70, SKIP, and abundant poly(A)-mRNA. The exact mechanism responsible for polyalanine toxicity in OPMD is unknown. Various intranuclear inclusion dependent and independent mechanisms have been proposed based on the major known function of PABPN1 in polyadenylation of mRNA and its shuttling from the nucleus to the cytoplasm. OPMD is one of the few triplet-repeat diseases for which the function of the mutated gene is known. Because of the increasing number of diseases caused by polyalanine expansions and the pathological overlap with CAG/polyglutamine diseases, what pathological insight is gained by the study of OPMD could lead to a better understanding of a much larger group of developmental and degenerative diseases.

Genetic heterogeneity in 30 German patients with oculopharyngeal muscular dystrophy

“…This is in line with the clinical observations in our patients. Moreover,we also did not find a correlation between disease onset and the number of (GCN)/polyalanine expansions consistent with previous studies [3,14] ( Table 2).…”

Oculopharyngeal muscular dystrophy (OPMD): analysis of the PABPN1 gene expansion sequence in 86 patients reveals 13 different expansion types and further evidence for unequal recombination as the mutational mechanism

“…In contrast, 2% of the French Canadian population carry the (GCG) 7 allele (Brais et al 1998) and a 1%-2% carrier prevalence has been estimated in North America, Europe and Japan (Brais 2003). In English OPMD patients, (GCG) 9 was the most common expansion, comprising 24% of mutations (27% of cases with no common haplotype), (GCG) 9 also being the most common mutation in the French Canadian population.…”

Two different PABPN1 expanded alleles in a Mexican population with oculopharyngeal muscular dystrophy arising from independent founder effects

“…Oculopharyngeal muscular dystrophy (OPMD, OMIM No 164300) is a distinct autosomal dominant myopathy characterised by a late-onset and progressive clinical triad of palpebral ptosis, dysphagia and proximal limb weakness 1. Once believed to be a cranial neuropathy, it has been established that the disease results from the selective affectation of specific muscular (palpebral, pharyngeal and proximal limb) groups.…”

“…OPMD was first described by Taylor in 1915, but it was not called OPMD until 1962 2 3. The disease has a worldwide distribution with significant variations in incidence in different geographical areas or ethnic groups, ranging from 1 in 1000 in the province of Quebec to 1 in 200 000 in France 1 4…”