14 NOVEL MUCOPOLYSACCHARIDOSIS IVA PRODUCING MUTATIONS IN GALNS GENE

Mucopolysaccharidosis IVA (MPS IVA) is an autosomal recessive disorder caused by a deficiency of the lysosomal N-acetylgalactosamine-6-sulfa te sulfatase, Here, we report our analysis of data on 21 patients of d iverse ethnic and geographic origins studied by SSCP and sequencing an alysis, Sixteen mutations were detected, including 14 new mutations (1 1 missense, one premature termination, one splice site alteration, and one cryptic site alteration), The donor splice site mutation (IVS4 1G-->A) predicts that normal splicing will be abolished and that trans lation would lead to an immediate premature termination (W141X), Anoth er novel nucleotide change outside the coding sequence is an intronic alteration (IVS9-42C-->T:ggtcggtgcggttggtgc) creating a potential cryp tic donor site, The nucleotide sequence surrounding this alteration is highly suggestive of a consensus donor splice site, All 12 missense a nd nonsense mutations were shown by transient expression to abolish or greatly reduce GALNS activity, thereby providing an explanation as to why they produce MPS IVA. All mutations were readily confirmed by res triction enzyme or by allelic specific oligonucleotide analysis (ASO), These findings, coupled with previously reported mutations, bring the total of different mutations to 41 among independent families with MP S IVA, illustrating the extensive allelic heterogeneity among mutation s producing MPS IVA. (C) Wiley-Liss, Inc.