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Novel missense ACAN gene variants linked to familial osteochondritis dissecans cluster in the C-terminal globular domain of aggrecan

Stattin, Eva-Lena ; Lindblom, Karin LU ; Struglics, André LU ; Önnerfjord, Patrik LU orcid ; Goldblatt, Jack ; Dixit, Abhijit ; Sarkar, Ajoy ; Randell, Tabitha ; Suri, Mohnish and Raggio, Cathleen , et al. (2022) In Scientific Reports 12. p.1-13
Abstract

The cartilage aggrecan proteoglycan is crucial for both skeletal growth and articular cartilage function. A number of aggrecan (ACAN) gene variants have been linked to skeletal disorders, ranging from short stature to severe chondrodyplasias. Osteochondritis dissecans is a disorder where articular cartilage and subchondral bone fragments come loose from the articular surface. We previously reported a missense ACAN variant linked to familial osteochondritis dissecans, with short stature and early onset osteoarthritis, and now describe three novel ACAN gene variants from additional families with this disorder. Like the previously described variant, these are autosomal dominant missense variants, resulting in single amino acid residue... (More)

The cartilage aggrecan proteoglycan is crucial for both skeletal growth and articular cartilage function. A number of aggrecan (ACAN) gene variants have been linked to skeletal disorders, ranging from short stature to severe chondrodyplasias. Osteochondritis dissecans is a disorder where articular cartilage and subchondral bone fragments come loose from the articular surface. We previously reported a missense ACAN variant linked to familial osteochondritis dissecans, with short stature and early onset osteoarthritis, and now describe three novel ACAN gene variants from additional families with this disorder. Like the previously described variant, these are autosomal dominant missense variants, resulting in single amino acid residue substitutions in the C-type lectin repeat of the aggrecan G3 domain. Functional studies showed that neither recombinant variant proteins, nor full-length variant aggrecan proteoglycan from heterozygous patient cartilage, were secreted to the same level as wild-type aggrecan. The variant proteins also showed decreased binding to known cartilage extracellular matrix ligands. Mapping these and other ACAN variants linked to hereditary skeletal disorders showed a clustering of osteochondritis dissecans-linked variants to the G3 domain. Taken together, this supports a link between missense ACAN variants affecting the aggrecan G3 domain and hereditary osteochondritis dissecans.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Scientific Reports
volume
12
article number
5215
pages
1 - 13
publisher
Nature Publishing Group
external identifiers
  • scopus:85127290500
  • pmid:35338222
ISSN
2045-2322
DOI
10.1038/s41598-022-09211-y
language
English
LU publication?
yes
additional info
© 2022. The Author(s).
id
d6ccb9a0-a53d-4172-bc86-2a636e246cfa
date added to LUP
2022-03-29 18:10:32
date last changed
2024-11-01 02:27:24
@article{d6ccb9a0-a53d-4172-bc86-2a636e246cfa,
  abstract     = {{<p>The cartilage aggrecan proteoglycan is crucial for both skeletal growth and articular cartilage function. A number of aggrecan (ACAN) gene variants have been linked to skeletal disorders, ranging from short stature to severe chondrodyplasias. Osteochondritis dissecans is a disorder where articular cartilage and subchondral bone fragments come loose from the articular surface. We previously reported a missense ACAN variant linked to familial osteochondritis dissecans, with short stature and early onset osteoarthritis, and now describe three novel ACAN gene variants from additional families with this disorder. Like the previously described variant, these are autosomal dominant missense variants, resulting in single amino acid residue substitutions in the C-type lectin repeat of the aggrecan G3 domain. Functional studies showed that neither recombinant variant proteins, nor full-length variant aggrecan proteoglycan from heterozygous patient cartilage, were secreted to the same level as wild-type aggrecan. The variant proteins also showed decreased binding to known cartilage extracellular matrix ligands. Mapping these and other ACAN variants linked to hereditary skeletal disorders showed a clustering of osteochondritis dissecans-linked variants to the G3 domain. Taken together, this supports a link between missense ACAN variants affecting the aggrecan G3 domain and hereditary osteochondritis dissecans.</p>}},
  author       = {{Stattin, Eva-Lena and Lindblom, Karin and Struglics, André and Önnerfjord, Patrik and Goldblatt, Jack and Dixit, Abhijit and Sarkar, Ajoy and Randell, Tabitha and Suri, Mohnish and Raggio, Cathleen and Davis, Jessica and Carter, Erin and Aspberg, Anders}},
  issn         = {{2045-2322}},
  language     = {{eng}},
  pages        = {{1--13}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Scientific Reports}},
  title        = {{Novel missense ACAN gene variants linked to familial osteochondritis dissecans cluster in the C-terminal globular domain of aggrecan}},
  url          = {{http://dx.doi.org/10.1038/s41598-022-09211-y}},
  doi          = {{10.1038/s41598-022-09211-y}},
  volume       = {{12}},
  year         = {{2022}},
}