Effect of ‘attenuated’ mutations in mucopolysaccharidosis IVA on molecular phenotypes of N‐acetylgalactosamine‐6‐sulfate sulfatase
- 17 September 2007
- journal article
- case report
- Published by Wiley in Journal of Inherited Metabolic Disease
- Vol. 30 (5), 758-767
- https://doi.org/10.1007/s10545-007-0702-z
Abstract
Mucopolysaccharidosis IVA is an autosomal recessive disease caused by the deficiency of N-acetylgalactosamine-6-sulfate sulfatase (GALNS). Mutation screening of the GALNS gene was performed for seven MPS IVA patients with attenuated phenotypes from three unrelated families. Four of 5 missense mutations identified in this study (p.F167V, p.R253W, p.R380S, p.P484S) and two reported (p.F97V, p.N204K), associated with attenuated phenotypes, were characterized using in vitro stable expression experiments, enzyme kinetic study, protein processing and structural analysis. The stably expressed mutant enzymes defining the attenuated phenotype exhibited a considerable residual activity (1.2–36.7% of the wild-type GALNS activity) except for p.R380S. Enzyme kinetic studies showed that p.F97V, p.F167V and p.N204K have lower affinity to the substrate compared with other mutants. The p.F97V enzyme was the most thermolabile at 55°C. Immunoblot analyses indicated a rapid degradation and/or an insufficiency in processing in the mutant proteins. Tertiary structure analysis revealed that although there was a tendency for ‘attenuated’ mutant residues to be located on the surface of GALNS, they have a different effect on the protein including modification of the hydrophobic core and salt-bridge formation and different potential energy. This study demonstrates that ‘attenuated’ mutant enzymes are heterogeneous in molecular phenotypes, including biochemical properties and tertiary structure.This publication has 40 references indexed in Scilit:
- International Morquio A Registry: Clinical manifestation and natural course of Morquio A diseaseJournal of Inherited Metabolic Disease, 2007
- Effect of Hunter disease (mucopolysaccharidosis type II) mutations on molecular phenotypes of iduronate‐2‐sulfatase: Enzymatic activity, protein processing and structural analysisJournal of Inherited Metabolic Disease, 2006
- Determinant factors of spectrum of missense variants in mucopolysaccharidosis IVA geneMolecular Genetics and Metabolism, 2006
- Mutation and polymorphism spectrum of the GALNS gene in mucopolysaccharidosis IVA (Morquio A)Human Mutation, 2005
- Identification of a common mutation in mucopolysaccharidosis IVA: correlation among genotype, phenotype, and keratan sulfateJournal of Human Genetics, 2004
- Mucopolysaccharidosis IV A: Assignment of the Human N-Acetylgalactosamine-6-Sulfate Sulfatase (GALNS) Gene to Chromosome 16q24Genomics, 1993
- Morquio disease: Isolation, characterization and expression of full-length cDNA for human N-acetylgalactosamine-6-sulfate sulfataseBiochemical and Biophysical Research Communications, 1991
- Efficient selection for high-expression transfectants with a novel eukaryotic vectorGene, 1991
- Clinical findings in 12 patients with MPS IV A (Morquio's disease)Clinical Genetics, 1988
- Amino Acid Difference Formula to Help Explain Protein EvolutionScience, 1974