Abstract

Background: Oculopharyngeal muscular dystrophy (OPMD) is a late onset hereditary myopathy of autosomal dominant transmission characterised by ptosis, dysphagia and limb weakness. The disease is caused by short heterozygous expansions of a (GCN)₁₀ triplet located in the first exon of the PABPN1 gene at chromosome 14q11.1. Most affected individuals from North America and Europe carry a mutant (GCN)₁₃ allele. Although evidence for a founder mutation effect has been shown in several populations with OPMD, analysis of large groups of patients from different ethnic backgrounds will help to identify the relative contribution of each allele to the disease and a possible genotype-phenotype correlation.

Methods: 22 unrelated patients with OPMD from Mexico, a previously uncharacterised population, were clinically and molecularly analysed. Detailed ophthalmological and clinical examinations were performed in each proband and molecular analysis of the PABPN1 gene was carried out by PCR amplification and allele-specific cloning/sequencing. Two single nucleotide polymorphisms (SNPs) linked to PABPN1 were determined in each individual and in a number of affected first-degree relatives.

Results: 15 subjects (68%) carried a mutant (GCN)₁₅ or (GCG)₁₁(GCA)₃(GCG) PABPN1 allele; the remaining 7 (32%) exhibited an abnormal (GCN)₁₃ or (GCG)₉(GCA)₃(GCG) allele. Analysis of two SNPs linked to PABPN1 strongly suggests that both expanded alleles originate from two independent founder effects. In addition, in this particular population the (GCN)₁₅ allele was associated with an earlier onset of the disease (mean 46.5 years) compared with the (GCN)₁₃ allele (mean 54.7 years).

Conclusion: The results of this study suggest that OPMD in the Mexican population is mostly due to (GCG)₁₁ or (GCG)₉ PABPN1 expanded alleles arising from two independent founder effect mutations. These findings add to the definition of the genetic features of the disease and to the establishment of a probable genotype-phenotype correlation.