dc.contributor.authorAjmal, Muhammad
dc.contributor.authorMir, Asif
dc.contributor.authorWahid, Sughra
dc.contributor.authorKhor, Chiea Chuen
dc.contributor.authorFoo, Jia Nee
dc.contributor.authorSiddiqi, Saima
dc.contributor.authorKauser, Mehran
dc.contributor.authorMalik, Salman Akbar
dc.contributor.authorNasir, Muhammad
dc.identifier.citationAjmal, M., Mir, A., Wahid, S., Khor, C. C., Foo, J. N., Siddiqi, S., et al. (2017). Identification and in silico characterization of a novel p.P208PfsX1 mutation in V-ATPase a3 subunit associated with autosomal recessive osteopetrosis in a Pakistani family. BMC Medical Genetics, 18(1), 148-.en_US
dc.description.abstractBackground: Osteopetrosis is a rare inherited bone disorder mainly described as an increased bone density caused by defective osteoclastic bone resorption. To date, genetic variants of eleven genes have been reported so far to be associated with different types of osteopetrosis. However, malignant infantile osteopetrosis, a lethal form of the disease, is mostly (50%) caused by mutation(s) in TCIRG1 gene. In this study, we investigated a consanguineous Pakistani family clinically and genetically to elucidate underlying molecular basis of the infantile osteopetrosis. Methods: DNA samples from five family members were subjected to SNP-array based whole genome homozygosity mapping. Data was analyzed and potentially pathogenic mutation was identified by Sanger sequencing of two affected as well as three phenotypically healthy individuals in the family. The significance of identified pathogenic variation and its impact on protein structure and function was studied using various bioinformatics tools. Results: DNA samples from five family members were subjected to genome-wide SNP array genotyping and homozygosity mapping which identified ~4 Mb region on chr11 harboring the TCIRG1 gene. Sanger sequencing unveiled a novel homozygous deletion c. 624delC in exon 6 of the TCIRG1 gene encodes a3 subunit of V-ATPase complex. The identified deletion resulted in a frame shift producing a truncated protein of 208 aa. In silico analysis of premature termination of the a3 subunit of V-ATPase complex revealed deleterious effects on the protein structure, predicting impaired or complete loss of V-ATPase function causing infantile osteopetrosis. Conclusions: Since a3 subunit of V-ATPase complex plays a crucial role in bone resorption process, structurally abnormal a3 subunit might have adversely affected bone resorption process, leading to infantile osteopetrosis in Pakistani family. Therefore, the present study not only expands the genotypic spectrum of osteopetrosis but also improve understandings of the role of V-ATPase a3 subunit in bone resorption process. Moreover, our findings should help in genetic counseling and provide further insight into the disease pathogenesis and potential targeted therapy.en_US
dc.format.extent9 p.en_US
dc.relation.ispartofseriesBMC Medical Geneticsen_US
dc.rights© 2017 The Author(s). Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.en_US
dc.subjectInfantile Malignant Osteopetrosisen_US
dc.subjectHuman TCIRG1 Geneen_US
dc.titleIdentification and in silico characterization of a novel p.P208PfsX1 mutation in V-ATPase a3 subunit associated with autosomal recessive osteopetrosis in a Pakistani familyen_US
dc.typeJournal Article
dc.contributor.schoolLee Kong Chian School of Medicineen_US
dc.description.versionPublished versionen_US

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