Heteroallelic missense mutations of the galactosamine‐6‐sulfate sulfatase (GALNS) gene in a mild form of Morquio disease (MPS IVA)

Abstract

Morquio disease (MPS IVA) is an autosomal recessive disorder caused by a deficiency of N-acetylgalactosamine-6-sulfate sulfatase (GALNS) activity. Patients commonly present in early infancy with growth failure, spondyloepiphyseal dysplasia, corneal opacification, and keratan sulfaturia, but milder forms have been described. We report on a patient who grew normally until age 5 years. Her keratan sulfaturia was not detected until adolescence, and she now has changes restricted largely to the axial skeleton. She has experienced only mildly impaired vision. At age 22, thin-layer chromatography of purified glycosaminoglycans showed some keratan sulfaturia. GALNS activity in fibroblast homogenate supernatants was 20 +/- 5% of controls (as compared to 5 +/- 3% of controls in severe MPS IVA, P < .003). Kinetic analysis of residual fibroblast GALNS activity in patient and parents revealed decreased K(m) and increased Vmax in the mother and daughter, but not in the father, compatible with compound heterozygosity. GALNS exons were amplified from patient genomic DNA and screened by SSCP. Two missense mutations, a C to T transition at position 335 (predicting R94C) and a T to G transversion at position 344 (predicting F97V), were found on sequencing an abnormally migrating exon 3 amplicon. Digestion of the amplicon with FokI and AccI restriction enzymes (specific for the R94C and F97V mutations, respectively) confirmed heterozygosity. In fibroblast transfection experiments, heterozygous R94C and F97V mutants independently expressed as severe and mild GALNS deficiency, respectively. We interpret these findings to indicate that our patient bears heteroallelic GALNS missense mutations, leading to GALNS deficiency and mild MPS IVA. Our findings expand the clinical and biochemical phenotype of MPS IVA, but full delineation of the genotype-phenotype relationship requires further study of native and transfected mutant cell lines.

Mucopolysaccharidosis IVA: characterization of a common mutation found in Finnish patients with attenuated phenotype

“…The length of the GALNS gene is 50 kb and contains 14 exons and 13 introns (Nakashima et al 1994). To date, more than 90 mutations have been identified in various ethnic populations (Tomatsu et al , 1995a(Tomatsu et al , 1995bOgawa et al 1995;Cole et al 1996;Fukuda et al 1996aFukuda et al , 1996bFukuda et al , 1997Bunge et al 1997;Yamada et al 1998;Terzioglu et al 2002). Some of these mutations are population-specific, such as I113F in the British-Irish population (Tomatsu et al 1995c), the double gene deletion in the Japanese population (Hori et al 1995), and G301C in the Colombian population .…”

Effect of ‘attenuated’ mutations in mucopolysaccharidosis IVA on molecular phenotypes of N‐acetylgalactosamine‐6‐sulfate sulfatase

“…T h ep . F 9 7 Vm u t a t i o nw a sr e p o r t e di na Canadian patient with an attenuated phenotype (Cole et al 1996). Phe-97 was located in a GALNS-specific residue (conserved only among different species of GALNS but not conserved between different sulfatases).…”