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Early‐onset metaphyseal chondrodysplasia type Schmid associated with a COL10A1 frame‐shift mutation and impaired trimerization of wild‐type α1(X) protein chains
Author(s) -
Mäkitie Outi,
Susic Miki,
Cole William G.
Publication year - 2010
Publication title -
journal of orthopaedic research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.041
H-Index - 155
eISSN - 1554-527X
pISSN - 0736-0266
DOI - 10.1002/jor.21161
Subject(s) - haploinsufficiency , mutant , wild type , nonsense mutation , mutant protein , mutation , biology , proband , nonsense , missense mutation , microbiology and biotechnology , chemistry , genetics , phenotype , gene
Both dominant‐negative and haploinsufficiency effects have been proposed in the pathogenesis of metaphyseal chondrodysplasia type Schmid (MCDS) due to nonsense and frame‐shift mutations of COL10A1 . This study examines these alternative effects. A proband with typical early‐onset MCDS was ascertained and COL10A1 sequencing undertaken. The assembly of trimeric collagen X molecules was studied using in vitro coupled transcription and translation of wild‐type and mutant α1(X) cDNAs. The proband was heterozygous for a unique COL10A1 mutation, c.1735_1739del5ins22. Mutant protein chains, with the corresponding p.G579fsX611 change, failed to spontaneously trimerize. When wild‐type α1(X) chains were translated alone, 57 ± 7% of the chains assembled into stable collagen X trimers. Trimerization of wild‐type chains was significantly reduced to 33 ± 6% when translated in 1:1 mixtures with p.G579fsX611 α1(X) chains. The protein assembly assay showed that the mutant chains exerted a dominant‐negative effect on collagen X assembly. Previous studies indicate that nonsense‐mediated decay, activation of endoplasmic reticulum, and unfolded protein responses as well as altered chondrocyte differentiation are the major determinants of phenotypic severity and age of presentation. We speculate that complete loss of mutant transcripts yields COL10A1 haploinsufficiency and late clinical presentation while incomplete loss of mutant transcripts yields dominant‐negative effects with early clinical presentation. © 2010 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 28:1497–1501, 2010