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Description of Joint Alterations Observed in a Family Carrying p.Asn453Ser COMP Variant: Clinical Phenotypes, In Silico Prediction of Functional Impact on COMP Protein and Stability, and Review of the Literature

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EA7451 BioConnecT, Normandie Université, UNICAEN, 14032 Caen, France
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Service de Rhumatologie, CHU de Caen, 14000 Caen, France
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EA4258 CERMN, Normandie Université, UNICAEN, 14032 Caen, France
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Department of Genetics and CNR-MAJ, Normandy Center for Genomic and Personalized Medicine, Normandie Université, UNIROUEN, Inserm U1245 and Rouen University Hospital, 76000 Rouen, France
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Délégation de la Recherche Clinique et de l’Innovation, CHU de Caen, 14000 Caen, France
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Service de Chirurgie Orthopédique, Clinique Saint-Martin, 14000 Caen, France
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Author to whom correspondence should be addressed.
Academic Editor: Vladimir N. Uversky
Biomolecules 2021, 11(10), 1460; https://doi.org/10.3390/biom11101460
Received: 17 August 2021 / Revised: 20 September 2021 / Accepted: 30 September 2021 / Published: 5 October 2021
(This article belongs to the Section Molecular Genetics)
The role of genetics in the development of osteoarthritis is well established but the molecular bases are not fully understood. Here, we describe a family carrying a germline mutation in COMP (Cartilage Oligomeric Matrix Protein) associated with three distinct phenotypes. The index case was enrolled for a familial form of idiopathic early-onset osteoarthritis. By screening potential causal genes for osteoarthritis, we identified a heterozygous missense mutation of COMP (c.1358C>T, p.Asn453Ser), absent from genome databases, located on a highly conserved residue and predicted to be deleterious. Molecular dynamics simulation suggests that the mutation destabilizes the overall COMP protein structure and consequently the calcium releases from neighboring calcium binding sites. This mutation was once reported in the literature as causal for severe multiple epiphyseal dysplasia (MED). However, no sign of dysplasia was present in the index case. The mutation was also identified in one of her brothers diagnosed with MED and secondary osteoarthritis, and in her sister affected by an atypical syndrome including peripheral inflammatory arthritis of unknown cause, without osteoarthritis nor dysplasia. This article suggests that this mutation of COMP is not only causal for idiopathic early-onset osteoarthritis or severe MED, but can also be associated to a broad phenotypic variability with always joint alterations. View Full-Text
Keywords: mutation; genetics; arthritis; osteoarthritis; COMP; dysplasia mutation; genetics; arthritis; osteoarthritis; COMP; dysplasia
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MDPI and ACS Style

Rochoux, Q.; Sopkova-de Oliveira Santos, J.; Marcelli, C.; Rovelet-Lecrux, A.; Chevallier, V.; Dutheil, J.-J.; Leclercq, S.; Boumédiene, K.; Baugé, C.; Aury-Landas, J. Description of Joint Alterations Observed in a Family Carrying p.Asn453Ser COMP Variant: Clinical Phenotypes, In Silico Prediction of Functional Impact on COMP Protein and Stability, and Review of the Literature. Biomolecules 2021, 11, 1460. https://doi.org/10.3390/biom11101460

AMA Style

Rochoux Q, Sopkova-de Oliveira Santos J, Marcelli C, Rovelet-Lecrux A, Chevallier V, Dutheil J-J, Leclercq S, Boumédiene K, Baugé C, Aury-Landas J. Description of Joint Alterations Observed in a Family Carrying p.Asn453Ser COMP Variant: Clinical Phenotypes, In Silico Prediction of Functional Impact on COMP Protein and Stability, and Review of the Literature. Biomolecules. 2021; 11(10):1460. https://doi.org/10.3390/biom11101460

Chicago/Turabian Style

Rochoux, Quitterie, Jana Sopkova-de Oliveira Santos, Christian Marcelli, Anne Rovelet-Lecrux, Virginie Chevallier, Jean-Jacques Dutheil, Sylvain Leclercq, Karim Boumédiene, Catherine Baugé, and Juliette Aury-Landas. 2021. "Description of Joint Alterations Observed in a Family Carrying p.Asn453Ser COMP Variant: Clinical Phenotypes, In Silico Prediction of Functional Impact on COMP Protein and Stability, and Review of the Literature" Biomolecules 11, no. 10: 1460. https://doi.org/10.3390/biom11101460

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