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SNOMEDCT: 22193007, 239869009;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 2p24.1 | {Osteoarthritis susceptibility 2} | 140600 | Autosomal dominant | 3 | MATN3 | 602109 |
A number sign (#) is used with this entry because of evidence that susceptibility to osteoarthritis-2 (OS2) is conferred by variation in the MATN3 gene (602109) on chromosome 2p24.
In the hand, osteoarthritis can develop in the distal interphalangeal and the first carpometacarpal (base of thumb) and proximal interphalangeal joints (Stefansson et al., 2003). Patients with osteoarthritis may have one, a few, or all of these sites affected. Heberden nodes are bony excrescences of the phalanges of the distal interphalangeal joints of the fingers (Stecher, 1955). They can be considered a variety of osteoarthrosis, or degenerative arthritis.
For a phenotypic description and a discussion of genetic heterogeneity of osteoarthritis, see OS1 (165720).
Stecher (1955) suggested that the disorder is sex-influenced so that it is dominant in women and recessive in males. It is also age-dependent, with penetrance complete after age 70. Stecher (1955) estimated that 27% of the general population is heterozygous and 3% homozygous.
Jonsson et al. (2003) conducted a study of the inheritance of hand osteoarthritis in Iceland by compiling a patient list through nationwide sources and cross-referencing this patient list with a comprehensive Icelandic genealogy database. They found that the average pairwise kinship coefficient of the patients was significantly higher than that for a control group and was proportional to the degree of both interphalangeal and thumb base (first carpometacarpal joint) involvement. The relative risk (RR) of HOA in sisters of women in this study was 2.0 (P less than 0.001), whereas the RR in spouses was not significantly different from that in controls. The RR increased with the severity of the disease. Thus, sisters of women with severe interphalangeal HOA had an RR of 5.0 and sisters of those with severe first carpometacarpal involvement had an RR of 6.9.
Stefansson et al. (2003) performed a genomewide linkage scan of hand osteoarthritis in Iceland. The best linkage peaks were on chromosomes 4q and 3p and on the short arm of chromosome 2. Genomewide significance was reached for a locus on chromosome 2 for patients with affected first carpometacarpal joints (lod = 4.97); this locus was also significant for patients with osteoarthritis in both carpometacarpal and distal interphalangeal joints (lod = 4.44). The peak lod score at this locus coincided with the MATN3 gene (602109), which encodes the noncollagenous cartilage extracellular matrix protein matrilin-3.
Heterogeneity
The evidence that distal interphalangeal joint (DIP) osteoarthritis (OA) represents a specific form of OA (Stecher, 1941; Cooper et al., 1996) with the strongest genetic component made it an ideal target for genetic studies aimed at dissecting the molecular background of OA. Leppavuori et al. (1999) conducted a genome scan in Finland using sibs with a severe, radiologically defined phenotype. In the initial genome screen, linkage analysis in 27 sibships gave a pairwise lod score greater than 1.00 with 9 of the 302 screening markers. In the second stage, additional markers and family members were genotyped in these chromosomal regions. Assuming a dominant mode of inheritance, the IL1R1 (147810) marker on 2q12 resulted in a maximum lod score of 2.34 at a recombination fraction of 0.0.
In 76 patients with hand osteoarthritis and 18 control individuals, Stefansson et al. (2003) screened the genomic sequence of the MATN3 gene and found a thr303-to-met mutation in MATN3 (T303M; 602109.0003), which had a frequency of slightly more than 2% in the patients with hand osteoarthritis and an RR of 2.1.
Cooper, C., Egger, P., Coggon, D., Hart, D. J., Masud, T., Cicuttini, F., Doyle, D. V., Spector, T. D. Generalized osteoarthritis in women: pattern of joint involvement and approaches to definition for epidemiological studies. J. Rheum. 23: 1938-1942, 1996. [PubMed: 8923371]
Jonsson, H., Manolescu, I., Stefansson, S. E., Ingvarsson, T., Jonsson, H. H., Manolescu, A., Gulcher, J., Stefansson, K. The inheritance of hand osteoarthritis in Iceland. Arthritis Rheum. 48: 391-395, 2003. [PubMed: 12571848] [Full Text: https://doi.org/10.1002/art.10785]
Leppavuori, J., Kujala, U., Kinnunen, J., Kaprio, J., Nissila, M., Heliovaara, M., Klinger, N., Partanen, J., Terwilliger, J. D., Peltonen, L. Genome scan for predisposing loci for distal interphalangeal joint osteoarthritis: evidence for a locus on 2q. Am. J. Hum. Genet. 65: 1060-1067, 1999. [PubMed: 10486325] [Full Text: https://doi.org/10.1086/302569]
Stecher, R. M. Heberden's nodes: heredity in hypertrophic arthritis of the finger joints. Am. J. Med. Sci. 201: 801, 1941.
Stecher, R. M. Heberden's nodes: a clinical description of osteo-arthritis of the finger joints. Ann. Rheum. Dis. 14: 1-10, 1955. [PubMed: 14362352] [Full Text: https://doi.org/10.1136/ard.14.1.1]
Stefansson, S. E., Jonsson, H., Ingvarsson, T., Manolescu, I., Jonsson, H. H., Olafsdottir, G., Palsdottir, E., Stefansdottir, G., Sveinbjornsdottir, G., Frigge, M. L., Kong, A., Gulcher, J. R., Stefansson, K. Genomewide scan for hand osteoarthritis: a novel mutation in matrilin-3. Am. J. Hum. Genet. 72: 1448-1459, 2003. [PubMed: 12736871] [Full Text: https://doi.org/10.1086/375556]