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

Background: 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 i...

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Main Authors: Ajmal, Muhammad, Mir, Asif, Wahid, Sughra, Khor, Chiea Chuen, Foo, Jia Nee, Siddiqi, Saima, Kauser, Mehran, Malik, Salman Akbar, Nasir, Muhammad
Other Authors: Lee Kong Chian School of Medicine (LKCMedicine)
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Language:English
Published: 2018
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Online Access:https://hdl.handle.net/10356/87516
http://hdl.handle.net/10220/44447
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spelling sg-ntu-dr.10356-875162020-11-01T05:20:49Z 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 Ajmal, Muhammad Mir, Asif Wahid, Sughra Khor, Chiea Chuen Foo, Jia Nee Siddiqi, Saima Kauser, Mehran Malik, Salman Akbar Nasir, Muhammad Lee Kong Chian School of Medicine (LKCMedicine) Infantile Malignant Osteopetrosis Human TCIRG1 Gene Background: 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. Published version 2018-02-22T09:06:33Z 2019-12-06T16:43:34Z 2018-02-22T09:06:33Z 2019-12-06T16:43:34Z 2017 Journal Article Ajmal, 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-. https://hdl.handle.net/10356/87516 http://hdl.handle.net/10220/44447 10.1186/s12881-017-0506-4 en BMC Medical Genetics © 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. 9 p. application/pdf
institution Nanyang Technological University
building NTU Library
continent Asia
country Singapore
Singapore
content_provider NTU Library
collection DR-NTU
language English
topic Infantile Malignant Osteopetrosis
Human TCIRG1 Gene
spellingShingle Infantile Malignant Osteopetrosis
Human TCIRG1 Gene
Ajmal, Muhammad
Mir, Asif
Wahid, Sughra
Khor, Chiea Chuen
Foo, Jia Nee
Siddiqi, Saima
Kauser, Mehran
Malik, Salman Akbar
Nasir, Muhammad
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
description Background: 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.
author2 Lee Kong Chian School of Medicine (LKCMedicine)
author_facet Lee Kong Chian School of Medicine (LKCMedicine)
Ajmal, Muhammad
Mir, Asif
Wahid, Sughra
Khor, Chiea Chuen
Foo, Jia Nee
Siddiqi, Saima
Kauser, Mehran
Malik, Salman Akbar
Nasir, Muhammad
format Article
author Ajmal, Muhammad
Mir, Asif
Wahid, Sughra
Khor, Chiea Chuen
Foo, Jia Nee
Siddiqi, Saima
Kauser, Mehran
Malik, Salman Akbar
Nasir, Muhammad
author_sort Ajmal, Muhammad
title 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
title_short 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
title_full 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
title_fullStr 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
title_full_unstemmed 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
title_sort 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
publishDate 2018
url https://hdl.handle.net/10356/87516
http://hdl.handle.net/10220/44447
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