Molecular heterogeneity in mucopolysaccharidosis IVA in Australia and Northern Ireland: nine novel mutations including T312S, a common allele that confers a mild phenotype.

Mucopolysaccharidosis IVA (MPS IVA) is an autosomal recessive lysosomal storage disorder caused by a genetic defect in N-acetylgalactosamine-6-sulfate sulfatase (GALNS). Previous studies of patients from a British-Irish population showed that the I113F mutation is the most common single mutation among MPS IVA patients and produces a severe clinical phenotype. We studied mutations in the GALNS gene from 23 additional MPS IVA patients (15 from Australia, 8 from Northern Ireland), with various clinical phenotypes (severe, 16 cases; intermediate, 4 cases; mild, 3 cases). We found two common mutations that together accounted for 32% of the 44 unrelated alleles in these patients. One is the T312S mutation, a novel mutation found exclusively in milder patients. The other is the previously described I113F that produces a severe phenotype. The I113F and T312S mutations accounted for 8 (18%) and 6 (14%) of 44 unrelated alleles, respectively. The relatively high residual GALNS activity seen when the T312S mutant cDNA is overexpressed in mutant cells provides an explanation for the mild phenotype in patients with this mutation. The distribution and relative frequencies of the I113F and T312S mutations in Australia corresponded to those observed in Northern Ireland and are unique to these two populations, suggesting that both mutations were probably introduced to Australia by Irish migrants during the 19th century. Haplotype analysis using 6 RFLPs provides additional data that the I113F mutation originated from a common ancestor. The other 9 novel mutations identified in these 23 patients were each limited to a single family. These data provide further evidence for extensive allelic heterogeneity in MPS IVA in British-Irish patients and provide evidence for their transmission to Australia by British-Irish migrants.