A Mutation in Cartilage Oligomeric Matrix Protein (Comp) Causes Early- Onset Osteoarthritis in a Large Kindred Study
Resource
ANNALS OF HUMAN GENETICS v.75 PART 5 pp.575-583
Journal
ANNALS OF HUMAN GENETICS
Journal Volume
v.75
Journal Issue
5
Pages
575-583
Date Issued
2011
Date
2011
Author(s)
MU, SHU-CHI
LIU, HWA-CHANG
WU, JER-YUARN
LEE, MING-TA MICHAEL
CHOU, CHING-HENG
CHEN, LIANG-KUANG
CHEN, YUAN-TSONG
Abstract
We performed a genome-wide linkage analysis to identify susceptibility loci in a large six-generation extended family previously reported with early-onset osteoarthritis ( OA) DNA sequencing was performed to investigate involvement of the COMP (Cartilage oligomeric matrix protein) gene in this family. The region covering D19S884, D19S226, and D19S 414 on chromosome 19p following genome-wide scan from 70 individuals of this kindred showed significant linkage, with a maximum point LOD (logarithm of the odds ratio) score of 2.51 at D19S226. Direct sequencing of the COMP gene, the most plausible candidate gene in the region, identified a c. 2152C > T substitution in exon 18 which resulted in a substitution of tryptophan for arginine at position 718 located in the C terminal globular domain of the gene product. A total of 26 individuals were identified with this mutation of which 21 affected individuals had the mutation, and the other five younger individuals (18.6 +/- 11.3 years of age) carried the mutation without symptoms. The results indicate that COMP is the disease susceptibility gene and the c.2152C > T mutation in exon 18 could cause early-onset OA phenotypes in this kindred, which is compatible with a previous report that this mutation also causes a mild form of multiple epiphyseal dysplasia (MED).
Subjects
Early-onset osteoarthritis
COMP
genome-wide linkage
phenotype
pseudoachondroplasia (PSACH)
multiple epiphyseal dysplasia (MED)