A common ancestral origin of the frequent and widespread 2299delG USH2A mutation

Usher syndrome type IIa is an autosomal recessive disorder characterized by mild-to-severe hearing loss and progressive visual loss due to retinitis p igmentosa. The mutation that most commonly causes Usher syndrome type IIa i s a 1-bp deletion, described as "2299delG," in the USH2A gene. The mutation has been identified in several patients from northern and southern Europe and from North America, and it has been found in single patients from South America, South Africa, and China. Various studies have reported a range of frequencies (.16-.44) among patients with Usher syndrome, depending on the geographic origin of the patients. The 2299delG mutation may be the one th at most frequently causes retinitis pigmentosa in humans. Given the high fr equencies and the wide geographic distribution of the mutation, it was of i nterest to determine whether the mutation resulted from an ancestral mutati onal event or represented a mutational hotspot in the USH2A gene. Haplotype analysis was performed on DNA samples from 116 unrelated patients with Ush er syndrome type IIa; the patients were from 14 countries and represented 1 48 2299delG alleles. On the basis of six single-nucleotide polymorphisms wi thin the USH2A gene, 12 core haplotypes were observed in a panel of normal chromosomes. However, in our analysis, only one core haplotype was found to be associated with the 2299delG mutation. The data indicate that the wides pread geographic distribution of the 2299delG mutation is the result of an ancestral mutation that has spread throughout Europe and into the New World as a result of migration.