Please use this identifier to cite or link to this item: https://doi.org/10.1186/s12881-017-0506-4
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
Authors: Ajmal, M
Mir, A
Wahid, S
Khor, C.C 
Foo, J.N
Siddiqi, S
Kauser, M
Malik, S.A
Nasir, M
Keywords: DNA
proton transporting adenosine triphosphate synthase
proton transporting adenosine triphosphate synthase
TCIRG1 protein, human
Article
autosomal recessive disorder
autosomal recessive osteopetrosis
bioinformatics
child
clinical article
complex formation
computer model
controlled study
exon
frameshift mutation
gene
gene deletion
genetic association
genetic code
genetic counseling
genetic variation
homozygosity
human
infant
male
mutational analysis
osteolysis
osteoporosis
Pakistani
pathogenesis
phenotype
protein assembly
protein structure
Sanger sequencing
single nucleotide polymorphism
structure activity relation
structure analysis
TCIRG1 gene
V ATPase a3 gene
Albers Schoenberg disease
amino acid sequence
computer simulation
diagnostic imaging
dna mutational analysis
genetics
genotype
homozygote
metabolism
molecular docking
mutation
Pakistan
pathophysiology
physiology
preschool child
Amino Acid Sequence
Bone Resorption
Child, Preschool
Computer Simulation
DNA Mutational Analysis
Exons
Genotype
Homozygote
Humans
Infant
Molecular Docking Simulation
Mutation
Osteopetrosis
Pakistan
Sequence Deletion
Vacuolar Proton-Translocating ATPases
Issue Date: 2017
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
Rights: Attribution 4.0 International
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).
Source Title: BMC Medical Genetics
URI: https://scholarbank.nus.edu.sg/handle/10635/181231
ISSN: 14712350
DOI: 10.1186/s12881-017-0506-4
Rights: Attribution 4.0 International
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