Novel mutation G324C in WNT1 mapped in a large Pakistani family with severe recessively inherited Osteogenesis Imperfecta

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Kausar , M , Siddiqi , S , Yaqoob , M , Mansoor , S , Makitie , O , Mir , A , Khor , C C , Foo , J N & Anees , M 2018 , ' Novel mutation G324C in WNT1 mapped in a large Pakistani family with severe recessively inherited Osteogenesis Imperfecta ' , Journal of Biomedical Science , vol. 25 , 82 . https://doi.org/10.1186/s12929-018-0481-x

Title: Novel mutation G324C in WNT1 mapped in a large Pakistani family with severe recessively inherited Osteogenesis Imperfecta
Author: Kausar, Mehran; Siddiqi, Saima; Yaqoob, Muhammad; Mansoor, Sajid; Makitie, Outi; Mir, Asif; Khor, Chiea Chuen; Foo, Jia Nee; Anees, Mariam
Other contributor: University of Helsinki, Children's Hospital




Date: 2018-11-17
Language: eng
Number of pages: 10
Belongs to series: Journal of Biomedical Science
ISSN: 1021-7770
DOI: https://doi.org/10.1186/s12929-018-0481-x
URI: http://hdl.handle.net/10138/299205
Abstract: IntroductionOsteogenesis imperfecta (OI) is a clinically and genetically heterogeneous disease with skeletal fragility and variable extra-skeletal manifestations. To date several point mutations in 18 different genes causing different types of OI have been identified. Mutations in WNT1 compromise activity of the osteoblasts leading to disturbed bone mass accrual, fragility fractures and progressive skeletal abnormalities. The present study was conducted to determine the underlying genetic cause of an autosomal recessive skeletal dysplasia in a large consanguineous family from Chinute, Pakistan.Materials and methodsBlood was collected from 24 individuals of affected family along with clinical data. Homozygosity mapping was performed to confirm consanguinity. SNPs were identified, followed by whole exome and Sanger sequencing. In silico characterization of WNT1 mutation was performed using multiple platforms.ResultsNine affected family members exhibited severe bone deformities, recurrent fractures, short stature and low bone mineral density. SNP array data revealed homozygous segments >1Mb in length accounting for 2.1-12.7% of the genome in affected individuals and their siblings and a single 6,344,821bp homozygous region in all affected individuals on chromosome 12q12-q13. This region includes two potential OI candidate genes WNT1 and VDR. We did whole-exome sequencing for both genes in two patients and identified a novel damaging missense mutation in exon 4 of WNT1: c.1168G>T (NM_005430) resulting in p.G324C. Sanger sequencing confirmed segregation of mutation with the disease in family.ConclusionWe report a novel mutation responsible for OI and our investigation expands the spectrum of disease-causing WNT1 mutations and the resulting OI phenotypes.
Subject: WNT signaling
Whole-exome sequencing
Osteoporosis
Osteogenesis imperfecta
FAST INTERACTION REFINEMENT
SURFACE-TOPOGRAPHY
MOLECULAR DOCKING
COMPUTED ATLAS
PROTEIN
FIREDOCK
5'-UTR
CASTP
3111 Biomedicine
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