Identification of Missense Mutation Pro77Arg As A Founder Mutation in Morquio-A Syndrome in Indian Gujarati Patel Ethnicity

Abstract

Background: Morquio A syndrome (MPS IVA) is a mucopolysaccharide group storage disorder caused due to the deficient activity of the lysosomal enzyme N-acetylgalactoseamine-6-sulfatase encoded by GALNS. The present study represents the mutation spectrum of GALNS in 25 Gujarati Patel patients of India clinically and biochemically confirmed with Morquio-A disorder.Methods: Urinary GAG quantitation and leucocyte enzyme assay was carried out in all 25 patients. This was followed by molecular characterization by amplification and sequencing of the exons and adjacent intronic regions of GALNS gene. Haplotype analysis was performed in patients showing p.P77R variant, using microsatellite markers D16S3121, D16S3026 and D16S3023 and SNPs.Results: We identified 11 mutations that include eight missense mutations: (p.L36R, p.D39G, p.P77R, p.C79R, pP125L, p.P151L, p.G255A and p.L350P), one splice site mutation: (c.121-7C>G), one small insertion: (c.1241_1242insA, p.I416HfsTer2) and one small deletion: (c.839_41delACA). Of these, three missense mutations (p.D39G, p.G255A and p.L350P), one splice site and the two indels mentioned above are novel. In the present study, we found maximum number of mutant alleles in exon 2, and of note, the variant p.P77R was seen in fourteen patients. Conclusion: p.P77R variant was predominantly found in Gujarati Patel community and the results of haplotype analysis indicated it to be the founder mutation in this community. Further, a study of 200 unrelated healthy control participants from Gujarat has identified this mutation in the heterozygous status in two individuals. Overall, our study suggests that p.P77R is likely to be a founder mutation for Morquio-A syndrome in Gujarati Patel ethnicity.