Structure, diversity, and evolution of the 45-bp VNTR in intron 5 of the USH1C gene

Usher syndrome type IC is a rare, autosomal recessive sensorineural disorder caused by mutations in the USH1C gene, which encodes a PDZ-domain protein named harmonin. The Acadian-specific 216G-->A mutation in exon 3 and a variant 9-repeat VNTR allele (designated VNTR(t,t)) in intron 5 are in complete linkage disequilibrium. (The usual form of the allele is referred to as VNTR(t).) To gain insight into the structure, diversity, and evolution of the VNTR, we analyzed individuals from seven different populations, as well as nonhuman primates and rodents. The 2-, 3-, and 6-repeat VNTR alleles were the most common. Four novel alleles containing 1, 5, 7, and 10 repeats were detected with frequencies of 0.002, 0.029, 0.005, and 0.001, respectively. The USH1C VNTR region is highly conserved among primates, but not between primates and rodents. Five unrelated individuals had a 3-repeat VNTR(t,t) allele. Haplotype analysis indicates that the 9-repeat VNTR(t,t) and the 3-repeat VNTR(t,t) alleles arose independently. However, the 9-repeat VNTR(t,t) and 6-repeat VNTR(t) alleles shared the same haplotype, suggesting an expansion from 6(t) to 9(t,t).