GALNS mutations in Indian patients with mucopolysaccharidosis IVA

Abstract

Mucopolysaccharidosis IV A (Morquio syndrome A, MPS IVA) is a lysosomal storage disease caused by the deficiency of N-acetylgalactosamine-6-sulfatase (GALNS). The mutation spectrum in this condition is yet to be determined in Indians. We aimed to analyze the mutations in the GALNS gene in Asian Indians with MPS IVA. All the exons and the adjacent intronic regions of the gene were amplified and sequenced in sixty-eight unrelated Indian families. We identified 136 mutant alleles comprising of 40 different mutations. We report twenty-two novel mutations that comprise of seventeen missense (p.Asn32Thr, p.Leu36Arg, p.Pro52Leu, p.Pro77Ser, p.Cys79Arg, p.His142Pro, p.Tyr191Asp, p.Asn204Thr, p.Gly188Ser, p.Phe216Ser, p.Trp230Cys, p.Ala291Ser, p.Gly317Arg, p.His329Pro, p.Arg386Ser, p.Glu450Gly, p.Cys501Ser), three splice-site variants (c.120+1G>C, c.1003-3C>G, c.1139+1G>A), one nonsense mutation (p.Gln414*) and one frameshift mutation (p.Pro420Leufs*440). Eighteen mutations have been reported earlier. Among these p.Ser287Leu (8.82%), p.Phe216Ser (7.35%), p.Asn32Thr (6.61%) and p.Ala291Ser (5.88%) were the most frequent mutations in Indian patients but were rare in the mutational profiles reported in other populations. These results indicate that the Indian patients may have a distinct mutation spectrum compared to those of other populations. Mutant alleles in exon 1, 7 and 8 accounted for 44.8% of the mutations, and sequencing of these exons initially may be a cost-effective approach in Asian Indian patients. This is the largest study on molecular analysis of patients with MPS IVA reported in the literature, and the first report from India.

KCNQ1 mutations associated with Jervell and Lange–Nielsen syndrome and autosomal recessive Romano–Ward syndrome in India—expanding the spectrum of long QT syndrome type 1

“…We hypothesize that the high rate of homozygous biallelic mutations (6/9; 67%) in the absence of consanguinity is due to the endogamous marriages within the same caste or community. Similar trends are also reported in other recessive disorders in India [Dalal et al, ; Bidchol et al, ].…”

Spectrum of SMPD1 mutations in Asian‐Indian patients with acid sphingomyelinase (ASM)‐deficient Niemann–Pick disease

“…It is known that even in the absence of actual consanguinity, inbreeding can lead to homozygosity for recessive mutations and thereby result in disease in the offspring [Pemberton et al, ]. This is not an uncommon phenomenon in many regions of India where inbreeding within small communities in quite prevalent and similar findings have been documented in previous molecular genetic studies from India [Dalal et al, ; Bidchol et al, ].…”

Medical genetics and genomic medicine in India: current status and opportunities ahead

“…Recent years have seen publication of genetic and mutation profiles for large case series of osteogenesis imperfecta, skeletal dysplasias, and lysosomal storage disorders. These studies have revealed the unique molecular profile of patients from the India with identification of many novel mutations not previously reported in other populations (Gorospe et al 2004;Pathak et al 2010;Sachdeva et al 2011Sachdeva et al , 2012Shukla et al 2011;Bashyam et al 2012;Dalal et al 2012;Mistri et al 2012;Bidchol et al 2014;Ankala et al 2015;Stephen et al 2015; A. Uttarilli, P. Ranganath, S.J.M. Nurul Jain, K.P.…”

“…Use of SNP microarray to identify regions of homozygosity and candidate genes in these regions is a strategy which can be successfully used in the consanguineous families (Stephen et al 2015). Some conditions found to be relatively common have been Van Der Knaap disease with a founder mutation in the Agarwal community from north western India, calpainopahy, recessive forms of Osteogenesis imperfecta, Progressive pseudorheumatoid arthropthy of childhood and Handigodu disease from a specific community in South India (Gorospe et al 2004;Pathak et al 2010;Sachdeva et al 2011Sachdeva et al , 2012Shukla et al 2011;Bashyam et al 2012;Dalal et al 2012;Bidchol et al 2014;Ankala et al 2015). However, the available data on monogenic malformation syndromes and metabolic disorders from India though extensive, represents only tip of the iceberg as a large population still does not have access to the clinical genetics services due to cost and limited number of genetic centers.…”