Screening of the COL2A1 mutation in idiopathic osteonecrosis of the femoral head

Abstract

Idiopathic osteonecrosis of the femoral head (idiopathic ONFH) is an ischemic disorder resulting in necrosis of the subchondral bone of the femoral head. COL2A1 mutations, including c.3508G>A, have been reported to be involved in its etiology. However, the etiological role of COL2A1 mutations in idiopathic ONFH remains controversial, because the pathology of idiopathic ONFH is ischemic necrosis, not epiphyseal dysplasia usually seen in the diseases caused by COL2A1 mutations. The purpose of this study is to examine whether COL2A1 mutations have causal relation with idiopathic ONFH or not. We recruited 1,451 Japanese patients with idiopathic ONFH, including steroid-, alcohol-, and neither steroid nor alcohol-associated (neither-associated) ONFH. The diagnosis was based on the criteria of the Japanese Research Committee on idiopathic ONFH of the Ministry of Health, Labour and Welfare. By whole-exome sequencing, entire COL2A1 coding regions and flanking introns were analyzed in 49 neither-associated ONFH patients. In addition, the c.3508G>A mutation of COL2A1 was checked in all idiopathic ONFH patients using the invader assay. Whole-exome sequencing did not detect any COL2A1 mutations in the 49 patients. The c.3508G>A mutation was not found in any of the 1,451 patients. In conclusion, COL2A1 is unlikely to cause idiopathic ONFH. Epiphyseal dysplasia of the femoral head caused by COL2A1 mutations may radiographically mimic idiopathic ONFH. COL2A1 mutations should prompt clinical re-evaluation of the patient's phenotype. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:768-774, 2017.

Association of Genes Variants in RANKL/RANK/OPG Signaling Pathway with the Development of Osteonecrosis of the Femoral Head in Chinese Population

“…A meta-analysis to assess the association of the 4b/a, G894T, and T786C polymorphisms of endothelial nitric oxide synthase with ONFH risk showed a significant correlation between allele a of the 4b/a polymorphism and idiopathic ONFH 20 . As chondrogenesis-specific transcription factor, collagen type II alpha-1 gene (COL2A1) mutations, including c.3508G > A, have been reported to be involved in idiopathic ONFH etiology 21 . OPG, as protein encoded by tumor necrosis factor superfamily11B (TNFRSF11B), is an osteoblast-secreted decoy receptor that functions as a negative regulator of bone resorption.…”

Mutation of COL2A1 in a Chinese Family with Presentations of Legg-Calvé-Perthes Disease

“…Genetic association studies suggest that mutations involved in cartilage constitution, bone metabolism, detoxification, coagulation system or vascular endothelium function might participate in the aetiology of osteonecrosis. [19][20][21][22] Based on an initial screening of exome sequencing and the subsequent confirmation of Sanger sequencing of this study, pathogenic mutations were identified in COL2A1 in a Chinese family with LCPD. The COL2A1 gene is localized at 12q13.11-q13.2 and about 30 kb in length with 54 exons, which provides a key element for the production of type II collagen.…”

“…[38][39][40] To date, the knowledge on the development of LCPD in humans is limited because of the vast number of mutations found in the COL2A1 gene and the variability in the clinical phenotype. [41,42] It is apparent that the process in which mutations in collagens alter connective tissues is complicated and cannot be described by one single pathway. In the future study, this pedigree can be extended by including the distal relatives of the family, which we believe can probably shed some light into the delineation of the pathological phenotype heterogeneity of this disease.…”

COL2A1 mutation (c.3508G>A) leads to avascular necrosis of the femoral head in a Chinese family: A case report

“…Unexpectedly, one family member with ANFH (II-1) had a normal genotype compared with the other affected family members; further investigation into the identification of the possible mutated genes is required. In recent decades, >200 mutations have been identified in the COL2A1 gene, including single substitution, splice-site mutations and partial deletions ( 2 , 3 , 8 ). Type II collagen is a major component of the articular cartilage, which reduces articular friction and absorbs load pressure during movement.…”

“…Numerous factors, including trauma, alcohol, steroids, coagulation disorders, sickle cell disease and fat embolism, have been reported to be implicated in the destruction of the femoral head ( 1 ). Avascular necrosis of the femoral head (ANFH), as a consequence of impaired blood supply, is a common type II collagenopathy that is associated with collagen type II α1 chain (COL2A1) mutations ( 2 , 3 ). The primary clinical manifestations of ANFH are limping gait, discrepancy in leg length and pain on exertion, which have a substantial effect on the quality of life of individuals ( 4 , 5 ).…”