Please use this identifier to cite or link to this item:
https://doi.org/10.1186/s12881-017-0506-4
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dc.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 | |
dc.contributor.author | Ajmal, M | |
dc.contributor.author | Mir, A | |
dc.contributor.author | Wahid, S | |
dc.contributor.author | Khor, C.C | |
dc.contributor.author | Foo, J.N | |
dc.contributor.author | Siddiqi, S | |
dc.contributor.author | Kauser, M | |
dc.contributor.author | Malik, S.A | |
dc.contributor.author | Nasir, M | |
dc.date.accessioned | 2020-10-27T10:17:27Z | |
dc.date.available | 2020-10-27T10:17:27Z | |
dc.date.issued | 2017 | |
dc.identifier.citation | Ajmal, M, Mir, A, Wahid, S, Khor, C.C, Foo, J.N, Siddiqi, S, Kauser, M, Malik, S.A, Nasir, M (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. ScholarBank@NUS Repository. https://doi.org/10.1186/s12881-017-0506-4 | |
dc.identifier.issn | 14712350 | |
dc.identifier.uri | https://scholarbank.nus.edu.sg/handle/10635/181231 | |
dc.description.abstract | 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. © 2017 The Author(s). | |
dc.rights | Attribution 4.0 International | |
dc.rights.uri | http://creativecommons.org/licenses/by/4.0/ | |
dc.source | Unpaywall 20201031 | |
dc.subject | DNA | |
dc.subject | proton transporting adenosine triphosphate synthase | |
dc.subject | proton transporting adenosine triphosphate synthase | |
dc.subject | TCIRG1 protein, human | |
dc.subject | Article | |
dc.subject | autosomal recessive disorder | |
dc.subject | autosomal recessive osteopetrosis | |
dc.subject | bioinformatics | |
dc.subject | child | |
dc.subject | clinical article | |
dc.subject | complex formation | |
dc.subject | computer model | |
dc.subject | controlled study | |
dc.subject | exon | |
dc.subject | frameshift mutation | |
dc.subject | gene | |
dc.subject | gene deletion | |
dc.subject | genetic association | |
dc.subject | genetic code | |
dc.subject | genetic counseling | |
dc.subject | genetic variation | |
dc.subject | homozygosity | |
dc.subject | human | |
dc.subject | infant | |
dc.subject | male | |
dc.subject | mutational analysis | |
dc.subject | osteolysis | |
dc.subject | osteoporosis | |
dc.subject | Pakistani | |
dc.subject | pathogenesis | |
dc.subject | phenotype | |
dc.subject | protein assembly | |
dc.subject | protein structure | |
dc.subject | Sanger sequencing | |
dc.subject | single nucleotide polymorphism | |
dc.subject | structure activity relation | |
dc.subject | structure analysis | |
dc.subject | TCIRG1 gene | |
dc.subject | V ATPase a3 gene | |
dc.subject | Albers Schoenberg disease | |
dc.subject | amino acid sequence | |
dc.subject | computer simulation | |
dc.subject | diagnostic imaging | |
dc.subject | dna mutational analysis | |
dc.subject | genetics | |
dc.subject | genotype | |
dc.subject | homozygote | |
dc.subject | metabolism | |
dc.subject | molecular docking | |
dc.subject | mutation | |
dc.subject | Pakistan | |
dc.subject | pathophysiology | |
dc.subject | physiology | |
dc.subject | preschool child | |
dc.subject | Amino Acid Sequence | |
dc.subject | Bone Resorption | |
dc.subject | Child, Preschool | |
dc.subject | Computer Simulation | |
dc.subject | DNA Mutational Analysis | |
dc.subject | Exons | |
dc.subject | Genotype | |
dc.subject | Homozygote | |
dc.subject | Humans | |
dc.subject | Infant | |
dc.subject | Molecular Docking Simulation | |
dc.subject | Mutation | |
dc.subject | Osteopetrosis | |
dc.subject | Pakistan | |
dc.subject | Sequence Deletion | |
dc.subject | Vacuolar Proton-Translocating ATPases | |
dc.type | Article | |
dc.contributor.department | BIOCHEMISTRY | |
dc.description.doi | 10.1186/s12881-017-0506-4 | |
dc.description.sourcetitle | BMC Medical Genetics | |
dc.description.volume | 18 | |
dc.description.issue | 1 | |
dc.description.page | 148 | |
Appears in Collections: | Elements Staff Publications |
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