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A Missense Mutation in the Aggrecan C-type Lectin Domain Disrupts Extracellular Matrix Interactions and Causes Dominant Familial Osteochondritis Dissecans

Stattin, Eva-Lena; Wiklund, Fredrik; Lindblom, Karin LU ; Önnerfjord, Patrik LU ; Jonsson, Bjorn-Anders; Tegner, Yelverton; Sasaki, Takako; Struglics, André LU ; Lohmander, Stefan LU and Dahl, Niklas, et al. (2010) In American Journal of Human Genetics 86(2). p.126-137
Abstract
Osteochondritis dissecans is a disorder in which fragments of articular cartilage and subchondral bone dislodge from the joint surface. We analyzed a five-generation family in which affected members had autosomal-dominant familial osteochondritis dissecans. A genome-wide linkage analysis identified aggrecan (ACAN) as a prime candidate gene for the disorder. Sequence analysis of ACAN revealed heterozygosity for a missense mutation (c.6907G > A) in affected individuals, resulting in a p.V2303M amino acid substitution in the aggrecan G3 domain C-type lectin, which mediates interactions with other proteins in the cartilage extracellular matrix. Binding studies with recombinant mutated and wild-type G3 proteins showed loss of fibulin-1,... (More)
Osteochondritis dissecans is a disorder in which fragments of articular cartilage and subchondral bone dislodge from the joint surface. We analyzed a five-generation family in which affected members had autosomal-dominant familial osteochondritis dissecans. A genome-wide linkage analysis identified aggrecan (ACAN) as a prime candidate gene for the disorder. Sequence analysis of ACAN revealed heterozygosity for a missense mutation (c.6907G > A) in affected individuals, resulting in a p.V2303M amino acid substitution in the aggrecan G3 domain C-type lectin, which mediates interactions with other proteins in the cartilage extracellular matrix. Binding studies with recombinant mutated and wild-type G3 proteins showed loss of fibulin-1, fibulin-2, and tenascin-R interactions for the V2303M protein. Mass spectrometric analyses of aggrecan purified from patient cartilage verified that V2303M aggrecan is produced and present in the tissue. Our results provide a molecular mechanism for the etiology of familial osteochondritis dissecans and show the importance of the aggrecan C-type lectin interactions for cartilage function in vivo. (Less)
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type
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publication status
published
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in
American Journal of Human Genetics
volume
86
issue
2
pages
126 - 137
publisher
Cell Press
external identifiers
  • wos:000274637200003
  • scopus:76049108551
ISSN
0002-9297
DOI
10.1016/j.ajhg.2009.12.018
language
English
LU publication?
yes
id
1f839683-d1e6-457c-84b4-8f0ccbd34f16 (old id 1568712)
date added to LUP
2010-03-17 13:25:58
date last changed
2018-06-17 03:28:03
@article{1f839683-d1e6-457c-84b4-8f0ccbd34f16,
  abstract     = {Osteochondritis dissecans is a disorder in which fragments of articular cartilage and subchondral bone dislodge from the joint surface. We analyzed a five-generation family in which affected members had autosomal-dominant familial osteochondritis dissecans. A genome-wide linkage analysis identified aggrecan (ACAN) as a prime candidate gene for the disorder. Sequence analysis of ACAN revealed heterozygosity for a missense mutation (c.6907G > A) in affected individuals, resulting in a p.V2303M amino acid substitution in the aggrecan G3 domain C-type lectin, which mediates interactions with other proteins in the cartilage extracellular matrix. Binding studies with recombinant mutated and wild-type G3 proteins showed loss of fibulin-1, fibulin-2, and tenascin-R interactions for the V2303M protein. Mass spectrometric analyses of aggrecan purified from patient cartilage verified that V2303M aggrecan is produced and present in the tissue. Our results provide a molecular mechanism for the etiology of familial osteochondritis dissecans and show the importance of the aggrecan C-type lectin interactions for cartilage function in vivo.},
  author       = {Stattin, Eva-Lena and Wiklund, Fredrik and Lindblom, Karin and Önnerfjord, Patrik and Jonsson, Bjorn-Anders and Tegner, Yelverton and Sasaki, Takako and Struglics, André and Lohmander, Stefan and Dahl, Niklas and Heinegård, Dick and Aspberg, Anders},
  issn         = {0002-9297},
  language     = {eng},
  number       = {2},
  pages        = {126--137},
  publisher    = {Cell Press},
  series       = {American Journal of Human Genetics},
  title        = {A Missense Mutation in the Aggrecan C-type Lectin Domain Disrupts Extracellular Matrix Interactions and Causes Dominant Familial Osteochondritis Dissecans},
  url          = {http://dx.doi.org/10.1016/j.ajhg.2009.12.018},
  volume       = {86},
  year         = {2010},
}