Identification of novel and known mutation in 19 patients with mucolipidosis type II and III from India and validation of novel method of screening for mucolipidosis-II and III screening

Mucolipidosis-II and III (ML-II and III) are an autosomal recessive lysosomal disorders caused due to impaired activity of lysosomal enzyme N-acetylglucosamine-1- phosphotransferase; composed of three subunits (α,β, γ) encoded by two genes-GNPTAB and GNPTG. Mutation in GNPTAB results in ML-II and ML-III(α/β) whereas mutation in GNPTGresults in ML-III(γ). As per HGMD database, 134 mutations in GNPTAB and 24 mutations in GNPTGgene have been reported from the different ethnic group, although disease-causing mutations are not known in Indian subjects. Hence, the present study was undertaken as a part of a national task force multicentric project to identify a molecular spectrum of GNPTAB and GNPTGgenes in Indian patients. Additionally, this study has enabled to validate indigenously developed screening testfor ML-II/III, to evaluate genotype-phenotype correlations and to establish common disease-causing mutations that can be utilized as a common molecular screening testin Indian patients. Present study consists of 19 children presented in the age range of 0.5 to 8 years. They have first screened for ML-II/III screening method followed by confirmative enzymes study from plasma. This was followed by mutation study using Sanger sequencing. The study has identified 16 mutations in 19 patients. Ten of them are novel, 9 in GNPTAB gene [p.T382P, p.R986H, p.W1201X, c.3336-1G > A, c.2675_2676dupT, c.2693_2694dupA, c.2954_2955dupCACAAAGT, c.73266_73473dup and c.1021_1023delCCA] and 1 in GNPTGgene [p.W108X]. Five previously reported mutations [p.R334Q, p.E968D, c.3335 + 1G > A, c.3503_3504delTC and g.65610_65610delA] in GNPTAB gene and one [p.C157X] in GNPTGgene were also identified. The most common mutation was frame-shift mutation c.3503_3504delTC, accounted for 41% of the patients. To conclude, c.3503_3504delTC seems to the common mutation in Indian patients. Our study also demonstrates that all patients who are screened positive were confirmed to have ML-II/III by enzymes and molecular study this validates our screening testfor ML-II/III with 100% sensitivity and specificity.