A missense mutation in the aggrecan C-type lectin domain disrupts extracellular matrix interactions and causes dominant familial osteochondritis dissecans

Eva-Lena Stattin; Fredrik Wiklund; Karin Lindblom; Patrik Onnerfjord; Björn-Anders Jonsson; Yelverton Tegner; Takako Sasaki; André Struglics; Stefan Lohmander; Niklas Dahl; Dick Heinegård; Anders Aspberg

doi:10.1016/j.ajhg.2009.12.018

A missense mutation in the aggrecan C-type lectin domain disrupts extracellular matrix interactions and causes dominant familial osteochondritis dissecans

Eva-Lena Stattin, Fredrik Wiklund, Karin Lindblom, Patrik Onnerfjord, Björn-Anders Jonsson, Yelverton Tegner, Takako Sasaki, André Struglics, Stefan Lohmander, Niklas Dahl, Dick Heinegård, Anders Aspberg

Cell Biology and Physiology

96 Citations (Scopus)

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.

Original language	English
Journal	American Journal of Human Genetics
Volume	86
Issue number	2
Pages (from-to)	126-37
Number of pages	11
ISSN	0002-9297
DOIs	https://doi.org/10.1016/j.ajhg.2009.12.018
Publication status	Published - 12 Feb 2010

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Stattin, E-L., Wiklund, F., Lindblom, K., Onnerfjord, P., Jonsson, B-A., Tegner, Y., Sasaki, T., Struglics, A., Lohmander, S., Dahl, N., Heinegård, D., & Aspberg, A. (2010). A missense mutation in the aggrecan C-type lectin domain disrupts extracellular matrix interactions and causes dominant familial osteochondritis dissecans. American Journal of Human Genetics, 86(2), 126-37. https://doi.org/10.1016/j.ajhg.2009.12.018

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 et al.

In: American Journal of Human Genetics, Vol. 86, No. 2, 12.02.2010, p. 126-37.

Research output: Contribution to journal › Journal article › Research › peer-review

Stattin, E-L, Wiklund, F, Lindblom, K, Onnerfjord, P, Jonsson, B-A, Tegner, Y, Sasaki, T, Struglics, A, Lohmander, S, Dahl, N, Heinegård, D & Aspberg, A 2010, 'A missense mutation in the aggrecan C-type lectin domain disrupts extracellular matrix interactions and causes dominant familial osteochondritis dissecans', American Journal of Human Genetics, vol. 86, no. 2, pp. 126-37. https://doi.org/10.1016/j.ajhg.2009.12.018

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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.",

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AU - Stattin, Eva-Lena

AU - Wiklund, Fredrik

AU - Lindblom, Karin

AU - Onnerfjord, Patrik

AU - Jonsson, Björn-Anders

AU - Tegner, Yelverton

AU - Sasaki, Takako

AU - Struglics, André

AU - Lohmander, Stefan

AU - Dahl, Niklas

AU - Heinegård, Dick

AU - Aspberg, Anders

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N2 - 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.

AB - 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.

U2 - 10.1016/j.ajhg.2009.12.018

DO - 10.1016/j.ajhg.2009.12.018

M3 - Journal article

C2 - 20137779

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JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

IS - 2

ER -

A missense mutation in the aggrecan C-type lectin domain disrupts extracellular matrix interactions and causes dominant familial osteochondritis dissecans

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