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Strong linkage on 2q33.3 to familial early-onset generalized osteoarthritis and a consideration of two positional candidate genes.
Eur J Hum Genet. 2006 Dec; 14(12):1280-7.EJ

Abstract

A genomewide screen was performed in four extended families with early-onset generalized osteoarthritis (FOA) without dysplasia. The FOA phenotype within these families shows a dominant Mendelian inheritance pattern and may represent common osteoarthritis (OA) at later ages. An initial locus was confirmed by three additional families and refined by 14 markers to a two-point logarithm of odds score of 6.05 (theta=0.00) for marker D2S155 at chromosome 2q33.3. This locus coincided with the highest multipoint nonparametric linkage score of 4.70 (P-value=0.0013) at marker D2S2358. Haplotype analysis of family members delineated a narrow region with a number of possible positional candidates, of which we investigate here the two most likely ones: PTHR2, encoding parathyroid hormone receptor 2, and FZD5, encoding frizzled receptor 5. For FZD5, we did not observe a segregating variant, however, for PTHR2, a missense variant (A225S) cosegregated with FOA in one family. The frequency of the PTHR2 variant was rare in a population-based sample, aged 55-70 years (N=1228, 0.4%). Of the 11 carriers, 36% showed generalized radiographic OA as compared to 23% in the remaining population. None of the other families that contributed to the linkage revealed a segregating variant. Together, we have identified a locus on chromosome 2q33.3 for FOA. Candidate gene analysis suggested a possible association of a PTHR2 variant with generalized radiographic OA; it is, however, unlikely the major disease gene for the observed linkage to the FOA phenotype.

Authors+Show Affiliations

Meulenbelt I
Molecular Epidemiology, Leiden University Medical Center, Einthovenweg 20, 2300 RC Leiden, The Netherlands. i.meulenbelt@lumc.nl
Min JL
No affiliation info available
van Duijn CM
No affiliation info available
Kloppenburg M
No affiliation info available
Breedveld FC
No affiliation info available
Slagboom PE
No affiliation info available

MeSH

Chromosomes, Human, Pair 2FemaleFrizzled ReceptorsGenetic Predisposition to DiseaseGenomeHumansMaleMutationOsteoarthritisPedigreeReceptor, Parathyroid Hormone, Type 2Receptors, G-Protein-Coupled

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

16912703

Citation

Meulenbelt, Ingrid, et al. "Strong Linkage On 2q33.3 to Familial Early-onset Generalized Osteoarthritis and a Consideration of Two Positional Candidate Genes." European Journal of Human Genetics : EJHG, vol. 14, no. 12, 2006, pp. 1280-7.
Meulenbelt I, Min JL, van Duijn CM, et al. Strong linkage on 2q33.3 to familial early-onset generalized osteoarthritis and a consideration of two positional candidate genes. Eur J Hum Genet. 2006;14(12):1280-7.
Meulenbelt, I., Min, J. L., van Duijn, C. M., Kloppenburg, M., Breedveld, F. C., & Slagboom, P. E. (2006). Strong linkage on 2q33.3 to familial early-onset generalized osteoarthritis and a consideration of two positional candidate genes. European Journal of Human Genetics : EJHG, 14(12), 1280-7.
Meulenbelt I, et al. Strong Linkage On 2q33.3 to Familial Early-onset Generalized Osteoarthritis and a Consideration of Two Positional Candidate Genes. Eur J Hum Genet. 2006;14(12):1280-7. PubMed PMID: 16912703.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Strong linkage on 2q33.3 to familial early-onset generalized osteoarthritis and a consideration of two positional candidate genes. AU - Meulenbelt,Ingrid, AU - Min,Josine L, AU - van Duijn,Cornelia M, AU - Kloppenburg,Margreet, AU - Breedveld,Ferdinand C, AU - Slagboom,P Eline, Y1 - 2006/08/16/ PY - 2006/8/17/pubmed PY - 2007/1/17/medline PY - 2006/8/17/entrez SP - 1280 EP - 7 JF - European journal of human genetics : EJHG JO - Eur J Hum Genet VL - 14 IS - 12 N2 - A genomewide screen was performed in four extended families with early-onset generalized osteoarthritis (FOA) without dysplasia. The FOA phenotype within these families shows a dominant Mendelian inheritance pattern and may represent common osteoarthritis (OA) at later ages. An initial locus was confirmed by three additional families and refined by 14 markers to a two-point logarithm of odds score of 6.05 (theta=0.00) for marker D2S155 at chromosome 2q33.3. This locus coincided with the highest multipoint nonparametric linkage score of 4.70 (P-value=0.0013) at marker D2S2358. Haplotype analysis of family members delineated a narrow region with a number of possible positional candidates, of which we investigate here the two most likely ones: PTHR2, encoding parathyroid hormone receptor 2, and FZD5, encoding frizzled receptor 5. For FZD5, we did not observe a segregating variant, however, for PTHR2, a missense variant (A225S) cosegregated with FOA in one family. The frequency of the PTHR2 variant was rare in a population-based sample, aged 55-70 years (N=1228, 0.4%). Of the 11 carriers, 36% showed generalized radiographic OA as compared to 23% in the remaining population. None of the other families that contributed to the linkage revealed a segregating variant. Together, we have identified a locus on chromosome 2q33.3 for FOA. Candidate gene analysis suggested a possible association of a PTHR2 variant with generalized radiographic OA; it is, however, unlikely the major disease gene for the observed linkage to the FOA phenotype. SN - 1018-4813 UR - https://www.unboundmedicine.com/medline/citation/16912703/Strong_linkage_on_2q33_3_to_familial_early_onset_generalized_osteoarthritis_and_a_consideration_of_two_positional_candidate_genes_ L2 - http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=332 DB - PRIME DP - Unbound Medicine ER -