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Am J Hum Genet. Sep 1995; 57(3): 556–563.
PMCID: PMC1801282

Mucopolysaccharidosis IVA: Identification of a Common Missense Mutation I113F in the N-Acetylgalactosamine-6-Sulfate Sulfatase Gene

Abstract

Mucopolysaccharidosis IVA is an autosomal recessive lysosomal storage disorder caused by a deficiency of N-acetylgalactosamine-6-sulfate sulfatase. The recent isolation and characterization of cDNA and genomic sequences encoding GALNS has facilitated identification of the molecular lesions that cause MPS IVA. We identified a common missense mutation among Caucasian MPS IVA patients. The mutation was originally detected by SSCP, and successive sequencing revealed an A→T transversion at nt 393. This substitution altered the isoleucine at position 113 to phenylalanine (I113F) in the 622 amino acid GALNS protein and was associated with a severe phenotype in a homozygote. Compound heterozygotes with one I113F-allele mutation have a wide range of clinical phenotypes. Transfection experiments in GALNS-deficient fibroblasts revealed that the mutation drastically reduces the enzyme activity of GALNS. Allele-specific oligonucleotide or SSCP analysis indicated that this mutation accounted for 22.5% (9/40) of unrelated MPS IVA chromosomes from 23 Caucasian patients, including 6 consanguineous cases. Of interest, the I1e 113→Phe substitution occurred in only Caucasian MPS IVA patients and in none of the GALNS alleles of 20 Japanese patients. These findings identify a frequent missense mutation among MPS IVA patients of Caucasian ancestry, that results in severe MPS IVA when homoallelic, and will facilitate molecular diagnosis of most such patients and identification of heterozygous carriers. In addition to this common mutation, 10 different point mutations and 2 small deletions were detected, suggesting allelic heterogeneity in GALNS gene.

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  • Baker E, Guo XH, Orsborn AM, Sutherland GR, Callen DF, Hopwood JJ, Morris CP. The morquio A syndrome (mucopolysaccharidosis IVA) gene maps to 16q24.3. Am J Hum Genet. 1993 Jan;52(1):96–98. [PMC free article] [PubMed]
  • Beck M, Glössl J, Grubisic A, Spranger J. Heterogeneity of Morquio disease. Clin Genet. 1986 Apr;29(4):325–331. [PubMed]
  • Fukuda S, Tomatsu S, Masue M, Sukegawa K, Iwata H, Ogawa T, Nakashima Y, Hori T, Yamagishi A, Hanyu Y, et al. Mucopolysaccharidosis type IVA. N-acetylgalactosamine-6-sulfate sulfatase exonic point mutations in classical Morquio and mild cases. J Clin Invest. 1992 Sep;90(3):1049–1053. [PMC free article] [PubMed]
  • Glössl J, Kresse H. A sensitive procedure for the diagnosis of N-acetyl-galactosamine-6-sulfate sulfatase deficiency in classical Morquio's disease. Clin Chim Acta. 1978 Aug 15;88(1):111–119. [PubMed]
  • Hori T, Tomatsu S, Nakashima Y, Uchiyama A, Fukuda S, Sukegawa K, Shimozawa N, Suzuki Y, Kondo N, Horiuchi T, et al. Mucopolysaccharidosis type IVA: common double deletion in the N-acetylgalactosamine-6-sulfatase gene (GALNS). Genomics. 1995 Apr 10;26(3):535–542. [PubMed]
  • Iwata H, Tomatsu S, Fukuda S, Uchiyama A, Rezvi GM, Ogawa T, Hori T, Nakashima Y, Yamagishi A, Sukegawa K, et al. Mucopolysaccharidosis IVA: polymorphic haplotypes and informative RFLPs in the Japanese population. Hum Genet. 1995 Mar;95(3):257–264. [PubMed]
  • Levran O, Desnick RJ, Schuchman EH. Niemann-Pick disease: a frequent missense mutation in the acid sphingomyelinase gene of Ashkenazi Jewish type A and B patients. Proc Natl Acad Sci U S A. 1991 May 1;88(9):3748–3752. [PMC free article] [PubMed]
  • Masuno M, Tomatsu S, Nakashima Y, Hori T, Fukuda S, Masue M, Sukegawa K, Orii T. Mucopolysaccharidosis IV A: assignment of the human N-acetylgalactosamine-6-sulfate sulfatase (GALNS) gene to chromosome 16q24. Genomics. 1993 Jun;16(3):777–778. [PubMed]
  • Nakashima Y, Tomatsu S, Hori T, Fukuda S, Sukegawa K, Kondo N, Suzuki Y, Shimozawa N, Orii T. Mucopolysaccharidosis IV A: molecular cloning of the human N-acetylgalactosamine-6-sulfatase gene (GALNS) and analysis of the 5'-flanking region. Genomics. 1994 Mar 1;20(1):99–104. [PubMed]
  • Ogawa T, Tomatsu S, Fukuda S, Yamagishi A, Rezvi GM, Sukegawa K, Kondo N, Suzuki Y, Shimozawa N, Orü T. Mucopolysaccharidosis IVA: screening and identification of mutations of the N-acetylgalactosamine-6-sulfate sulfatase gene. Hum Mol Genet. 1995 Mar;4(3):341–349. [PubMed]
  • Orita M, Suzuki Y, Sekiya T, Hayashi K. Rapid and sensitive detection of point mutations and DNA polymorphisms using the polymerase chain reaction. Genomics. 1989 Nov;5(4):874–879. [PubMed]
  • Polten A, Fluharty AL, Fluharty CB, Kappler J, von Figura K, Gieselmann V. Molecular basis of different forms of metachromatic leukodystrophy. N Engl J Med. 1991 Jan 3;324(1):18–22. [PubMed]
  • Scott HS, Nelson PV, Cooper A, Wraith JE, Hopwood JJ, Morris CP. Mucopolysaccharidosis type I (Hurler syndrome): linkage disequilibrium indicates the presence of a major allele. Hum Genet. 1992 Mar;88(6):701–702. [PubMed]
  • Sukegawa K, Orii T. Residual activity in fibroblasts from two brothers with the late-onset form of N-acetylgalactosamine-6-sulphate sulphatase deficiency. J Inherit Metab Dis. 1982;5(4):231–232. [PubMed]
  • Tomatsu S, Fukuda S, Cooper A, Wraith JE, Uchiyama A, Hori T, Nakashima Y, Yamada N, Sukegawa K, Kondo N, et al. Mucopolysaccharidosis IVA: structural gene alterations identified by Southern blot analysis and identification of racial differences. Hum Genet. 1995 Apr;95(4):376–381. [PubMed]
  • Tomatsu S, Fukuda S, Iwata H, Ogawa T, Sukegawa K, Orii T. XhoI and SphI RFLPs in the GALNS gene. Hum Mol Genet. 1994 Jul;3(7):1208–1208. [PubMed]
  • Tomatsu S, Fukuda S, Masue M, Sukegawa K, Fukao T, Yamagishi A, Hori T, Iwata H, Ogawa T, Nakashima Y, et al. Morquio disease: isolation, characterization and expression of full-length cDNA for human N-acetylgalactosamine-6-sulfate sulfatase. Biochem Biophys Res Commun. 1991 Dec 16;181(2):677–683. [PubMed]
  • Tomatsu S, Fukuda S, Ogawa T, Kato Z, Isogai K, Kondo N, Suzuki Y, Shimozawa N, Sukegawa K, Orii T. A novel splice site mutation in intron 1 of the GALNS gene in a Japanese patient with mucopolysaccharidosis IVA. Hum Mol Genet. 1994 Aug;3(8):1427–1428. [PubMed]
  • Tomatsu S, Fukuda S, Uchiyama A, Hori T, Nakashima Y, Sukegawa K, Kondo N, Suzuki Y, Shimozawa N, Orii T. Polymerase chain reaction detection of two novel human N-acetylgalactosamine-6-sulfate sulfatase gene polymorphisms by single-strand conformation polymorphism analysis or by StyI and StuI cleavages. Hum Genet. 1995 Feb;95(2):243–244. [PubMed]
  • Tsuji S, Choudary PV, Martin BM, Stubblefield BK, Mayor JA, Barranger JA, Ginns EI. A mutation in the human glucocerebrosidase gene in neuronopathic Gaucher's disease. N Engl J Med. 1987 Mar 5;316(10):570–575. [PubMed]
  • Zhang Z, Kolvraa S, Zhou Y, Kelly DP, Gregersen N, Strauss AW. Three RFLPs defining a haplotype associated with the common mutation in human medium-chain acyl-CoA dehydrogenase (MCAD) deficiency occur in Alu repeats. Am J Hum Genet. 1993 Jun;52(6):1111–1121. [PMC free article] [PubMed]

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