Novel mutation in Teneurin 3 found to co-segregate in all affecteds in a multi-generation family with developmental dysplasia of the hip
| Autor: | Andrzej Fertala, Dietmar J. Kappes, Javad Parvizi, Jayati Mookerjee-Basu, Theresa A. Freeman, George J. Feldman |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Male Mutant Arthritis Nerve Tissue Proteins Bioinformatics medicine.disease_cause Osteochondrodysplasias 03 medical and health sciences Mice 0302 clinical medicine Medicine Animals Humans Orthopedics and Sports Medicine Femur Exome Hip Dislocation Congenital Teneurin 030222 orthopedics Mutation biology business.industry Membrane Proteins medicine.disease Chondrogenesis Phenotype 030104 developmental biology biology.protein Female Joint Diseases business |
| Zdroj: | Journal of orthopaedic research : official publication of the Orthopaedic Research Society. 37(1) |
| ISSN: | 1554-527X 1837-2139 |
| Popis: | DDH is a debilitating condition characterized by incomplete formation of the acetabulum leading to dislocation of the hip, suboptimal joint function and accelerated wear of the articular cartilage resulting in early onset crippling arthritis of the hip in 20-40 year olds. Current diagnostic tests in newborns using physical manipulation of the femur or ultrasound either under or over-diagnose this condition. Developing an accurate, cost effective diagnostic test is a goal of this study. To better understand the biologic pathways involved in acetabular development, DNA from severely affected individuals in a four generation family that showed inter-generational transmission of the disorder was isolated and whole exome sequenced. A novel A to C transversion at position 183721398 on human chromosome four was found to co-segregate with the affected phenotype in this family. This mutation encodes a glutamine to proline change at position 2665 in the Teneurin 3 (TENM3) gene and was judged damaging by four prediction programs. Eight week old knock-in mutant mice show delayed development of the left acetabulum and the left glenoid fossa as shown by the presence of more Alcian blue staining on the socket rims of both the hip and the shoulder. We hypothesize that mutated TENM3 will slow chondrogenesis. MMP13 has been shown to impair extracellular matrix remodeling and suppress differentiation. Bone marrow cells from the knock-in mouse were found to overexpress MMP13 with or without BMP2 stimulation. This variant may elucidate pathways responsible for normal hip development and become part of an accurate test for DDH. © 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res. |
| Databáze: | OpenAIRE |
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