Mucopolysaccharidosis IVA (Morquio A): Identification of novel common mutations in the N-acetylgalactosamine-6-sulfate sulfatase (GALNS) gene in Italian patients

Abstract

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.

Mucopolysaccharidosis IVA mutations in Chinese patients: 16 novel mutations

“…The only difference in the haplotypes could be caused by a recurrent transition of rs35137494. Therefore, similar to the situations previously described in Italian 17 and Finnish 31 patients, the mutation spectrum in Chinese patients is unique because most mutations are Chinese-unique and family-specific, whereas one mutation (p.G340D) exists in a higher proportion (16.7%). The unique mutation spectrum is in agreement with the fact that Chinese were comparatively isolated genetically in history due to its geographic location and culture.…”

“…Mutation spectrums have been created in some populations and distinctions were observed. [9][10][11][12][13][14][15][16][17][18][19] Although one-fifth of the world population is composed of Chinese, the mutation spectrum in Chinese MPS IVA patients is not available.…”

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

“…The p.M1? was observed previously in Italian patients with severe form (Tomatsu et al 2004b). The mutation p.P484S, located in exon 13, caused the change of CCC to TCC.…”

Descriptively quantitative relationship between mutated N‐acetylgalactosamine‐6‐sulfatase and mucopolysaccharidosis IVA

“…So we have q 0 ¼ 3, After mutation, an amino acid will be changed, so will its distribution probability. For example, a mutation at position 386 changes arginine to cysteine, 86,87 and we can see this change in Table I. For arginines, there are 25 and 24 before and after mutation with distribution probabilities of 0.0446 and 0.0714, so this mutation increases arginine distribution probability.…”