- 作者: Mehran Kausar, Saima Siddiqi, Muhammad Yaqoob, Sajid Mansoor, Outi Makitie, Asif Mir, Chiea Chuen Khor, Jia Nee Foo and Mariam Anees
- 作者服務機構: 1.Department of Biochemistry, Faculty of Biological Sciences, Quaid-i-Azam University, University Road, Islamabad, Post code 45320, Pakistan 2.Institute of Biomedical and Genetic Engineering (IBGE) Islamabad, Islamabad, 44000, Pakistan 3.Department of Genetics, Children Hospital, Lahore, Pakistan 4.Atta-ur-Rehman School of Applied Biosciences, NUST, Islamabad, Pakistan 5.Department of Microbiology, Faculty of Life Sciences, University of Central Punjab, Lahore, Pakistan 6.Children’s Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland 7.Folkhälsan Institute of Genetics, Helsinki, Finland 8.Department of Bioinformatics & Biotechnology, Faculty of Basic and Applied Sciences, International Islamic University (IIU), H-10, Islamabad, 44000, Pakistan 9.Human Genetics, Genome Institute of Singapore, A*STAR, Singapore, 138672, Singapore 10.Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, 308232, Singapore
- 中文摘要:
- 英文摘要:
Introduction
Osteogenesis 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 methods
Blood 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.
Results
Nine affected family members exhibited severe bone deformities, recurrent fractures, short stature and low bone mineral density. SNP array data revealed homozygous segments > 1 Mb in length accounting for 2.1–12.7% of the genome in affected individuals and their siblings and a single 6,344,821 bp 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.
Conclusion
We report a novel mutation responsible for OI and our investigation expands the spectrum of disease-causing WNT1 mutations and the resulting OI phenotypes. - 中文關鍵字:
- 英文關鍵字: WNT signaling, Whole-exome sequencing, Osteoporosis, Osteogenesis imperfecta