Mucopolysaccharidosis IVA (MPS IVA) is a lysosomal storage disorder caused by the deficiency of N-acetylgalactosamine-6-sulfate sulfatase (GALNS). Mutation screening of the GALNS gene was performed by RT-PCR with one amplicon and direct sequence analyses using cDNA samples from 15 Italian MPS IVA patients. Each mutation was confirmed at the genomic level. In this study, 13 different gene mutations with four common mutations (over 10% of mutant alleles) were identified in 12 severe and three milder (attenuated) MPS IVA patients. The gene alterations in 12 out of 13 were found to be point mutations and only one mutation was deletion. Ten of 13 mutations were novel. The c.1070C>T (p.Pro357Leu) mutation coexisted with c.1156C>T (p.Arg386Cys) mutation on the same allele. Together they accounted for 100% of the 30 disease alleles of the patients investigated. Four common mutations accounted for 70% of mutant alleles investigated. Urine keratan sulfate (KS) concentrations were elevated in all patients investigated. These data provide further evidence for extensive allelic heterogeneity and importance of relation among genotype, phenotype, and urine KS excretion as a biomarker in MPS IVA.
Copyright 2004 Wiley-Liss, Inc.