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A matrilin‐3 mutation associated with osteoarthritis does not affect collagen affinity but promotes the formation of wider cartilage collagen fibrils
Author(s) -
Otten Christiane,
Hansen Uwe,
Talke Anja,
Wagener Raimund,
Paulsson Mats,
Zaucke Frank
Publication year - 2010
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.21182
Subject(s) - fibrillogenesis , endoplasmic reticulum , fibril , extracellular matrix , cartilage , osteoarthritis , mutation , biology , cartilage oligomeric matrix protein , microbiology and biotechnology , chemistry , biochemistry , medicine , pathology , anatomy , gene , alternative medicine
Mutations in matrilin‐3 have been associated with common skeletal diseases like osteoarthritis as well as with the rare chondrodysplasias MED and SEMD. We have previously shown that the mutations p.R116W and p.C299S, associated with MED and SEMD, respectively, cause retention of matrilin‐3 within the endoplasmic reticulum of primary chondrocytes, while the mutation associated with osteoarthritis, p.T298M, does not hinder secretion. The present study focused on the consequences of the p.T298M mutation on the structure of matrilin‐3 and on the role of matrilin‐3 in the formation of a functional extracellular matrix. Analysis of recombinant full‐length matrilin‐3 revealed that the p.T298M mutation does not influence oligomerization of matrilin‐3 or its proteolytic processing by ADAMTS‐4 and ‐5. Nevertheless, structural analyses indicate local conformational changes. These changes do not affect the affinity for collagens II, IX, XI, or COMP, but have a major impact on the in vitro fibrillogenesis of collagen II/IX/XI heterofibrils. Hum Mutat 31:254–263, 2010. © 2010 Wiley‐Liss, Inc.