Mutations in ARSB in MPS VI patients in India

Abstract

Mucopolysaccharidosis VI (MPS VI) is an autosomal recessive inborn error of metabolism caused by mutations in the arylsulfatase B gene (ARSB) and consequent deficient activity of ARSB, a lysosomal enzyme. We present here the results of a study undertaken to identify the mutations in ARSB in MPS VI patients in India. Around 160 ARSB mutations, of which just 4 are from India, have been reported in the literature. Our study covered nine MPS VI patients from eight families. Both familial mutations were found in seven families, and only one mutation was found in one family. Seven mutations were found — four novel (p.G38_G40del3, p.C91R, p.L98R and p.R315P), two previously reported from India (p.D53N and p.W450C), and one reported from outside India (p.R160Q). One mutation, p.W450C, was present in two families, and the other six mutations were present in one family each. Analysis of the molecular structure of the enzyme revealed that most of these mutations either cause loss of an active site residue or destabilize the structure of the enzyme. The only previous study on mutations in ARSB in Indian MPS VI patients, by Kantaputra et al. 2014 [1], reported four novel mutations of which two (p.D53N and p.W450C) were found in our study as well. Till date, nine mutations have been reported from India, through our study and the Kantaputra study. Eight out of these nine mutations have been found only in India. This suggests that the population studied by us might have its own typical set of mutations, with other populations equally likely to have their own set of mutations.

Mucopolysaccharidosis type VI (MPS VI) and molecular analysis: Review and classification of published variants in theARSBgene

“…Arylsulfatase B includes two domains; a larger N‐terminal domain and a smaller C‐terminal domain; and reported to function as a monomer (Mathew et al., ; McGovern, Vine, Haskins, & Desnick, ). ASB contains two conserved sulfatase regions near the N‐terminal (Bond et al., ; Peters et al., ).…”

“…c.479G>A [p.(Arg160Gln)] results from a transition in a CpG dinucleotide (Litjens & Hopwood, ). p.(Arg160Gln) has been observed in both heterozygous and homozygous states (Kantaputra et al., ; Mathew et al., ; Villani et al., ; Voskoboeva et al., ). The mechanism by which the arginine‐to‐glutamine alteration contributes to disease is not well understood, as its effect on enzyme structure is predicted to be minimal (Mathew et al., ).…”

“…Patients with two p.(Arg315Gln) alleles demonstrate a range of clinical phenotypes, from intermediate to classically severe (Di Natale et al., ; Karageorgos et al., ; Petry et al., ; Villani et al., ). Arg315 is predicted to form a salt bridge with Asp466, as well as hydrogen bonds with Gly448 and Glu483 (Garrido et al., ; Mathew et al., ). Thus, the arginine‐to‐glutamine alteration is predicted to hinder both substrate binding and metal ion coordination (Villani et al., ).…”

“…Thus, the arginine‐to‐glutamine alteration is predicted to hinder both substrate binding and metal ion coordination (Villani et al., ). Two additional mutations at Arg315 have also been reported—the missense mutation p.(Arg315Pro) and the nonsense mutation p.(Arg315*), which produces a polypeptide roughly one‐third the length of wild‐type and is predicted to lack enzymatic activity (Di Natale et al., ; Ferla et al., ; Lin et al., ; Mathew et al., ; Villani et al., ). Both p.(Arg315Gln) and p.(Arg315Pro) result from an alteration in the CpG dinucleotide c.944G, suggesting this nucleotide may be a mutational hot spot in ARSB (Litjens & Hopwood, ; Mathew et al., ).…”

“…Arylsulfatase B includes two domains; a larger N-terminal domain and a smaller C-terminal domain; and reported to function as a monomer (Mathew et al, 2015;McGovern, Vine, Haskins, & Desnick, 1982).…”