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
| Autor: | Saima Siddiqi, Asif Mir, Muhammad Nasir, Chiea Chuen Khor, Salman Akbar Malik, Muhammad Ajmal, Mehran Kauser, Sughra Wahid, Jia Nee Foo |
|---|---|
| Přispěvatelé: | Lee Kong Chian School of Medicine (LKCMedicine) |
| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Infantile malignant osteopetrosis V0 domain DNA Mutational Analysis V-ATPase medicine.disease_cause 0302 clinical medicine Pakistan Genetics (clinical) Sequence Deletion Genetics Sanger sequencing Mutation Homozygote Exons Disease gene identification Human TCIRG1 Gene Molecular Docking Simulation 030220 oncology & carcinogenesis Child Preschool Osteopetrosis symbols Human TCIRG1 gene SNP array Research Article Vacuolar Proton-Translocating ATPases lcsh:Internal medicine Genotype lcsh:QH426-470 Biology Frameshift mutation 03 medical and health sciences symbols.namesake Infantile Malignant Osteopetrosis medicine Humans Computer Simulation a3 subunit Amino Acid Sequence Bone Resorption lcsh:RC31-1245 Infant Increased Bone Density medicine.disease lcsh:Genetics 030104 developmental biology |
| Zdroj: | BMC Medical Genetics, Vol 18, Iss 1, Pp 1-9 (2017) BMC Medical Genetics |
| ISSN: | 1471-2350 |
| Popis: | 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. Electronic supplementary material The online version of this article (10.1186/s12881-017-0506-4) contains supplementary material, which is available to authorized users. |
| Databáze: | OpenAIRE |
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