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Genetic Aspects of Familial Osteoarthritis

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Genetic Aspects of Familial Osteoarthritis Annals of the Rheumatic Diseases 1994; 53: 789-797 789 REVIEW Ann Rheum Dis: first published as 10.1136/ard.53.12.789 on 1 December 1994. Downloaded from Genetic aspects of familial osteoarthritis Sergio A Jimenez, Rita M Dharmavaram Human osteoarthritis (OA) is a heterogeneous cartilage may be responsible for the premature and multifactorial disease characterised by the and generalised degeneration of the tissue progressive deterioration of the cartilage of matrix. The abnormal genes could include the diarthrodial joints. Multiple aetiological and genes for cartilage matrix macromolecules, for pathogenetic mechanisms have been impli- enzymes involved in the biosynthesis of matrix, cated in its development and progression.' In for hormone and growth factor receptors in many instances OA is an acquired process chondrocytes, or for enzymes involved in the secondary to various metabolic, mechani- metabolic degradation of the tissue. Recent cal, or inflammatory-immunological events. evidence, however, suggests that the genes However, it has long been recognised that encoding the collagenous components of several distinct forms are inherited as dominant cartilage matrix are the most likely candidates. traits with a Mendelian pattern.2 3 The most The collagens represent the most abundant common form of inherited OA is characterised protein of articular cartilage matrix, com- by the presence of Heberden's and Bouchard's prising about 50% of the dry weight of the nodes and the concentric or uniform de- tissue. These molecules play a crucial role generation of the articular cartilage of several in the maintenance of the biomechanical joints, particularly the hips and knees.4 Many properties of cartilage, being responsible for studies have examined the genetic factors that the tensile strength and shear stiffness of the may be associated with either development or tissue. The remarkable complexity of the severity of this form of OA. Analysis of the organisation of the collagenous components in frequencies of HLA antigens in various popu- articular cartilage has recently become lations of patients affected have yielded apparent'7 18 and at least five different collagen conflicting results,5-9 although in one study an types representing the products encoded by at increased frequency of the HLA-A1B8 least 10 distinct genes have been recognised in phenotype was observed.9 This study also the tissue. Although the cartilage-specific type examined the frequency of (x l-antitrypsin II collagen is the most abundant collagen http://ard.bmj.com/ phenotypes in these individuals and found a species in the tissue, it is very likely that the significant increase in the MZ phenotype,9 other collagen types (types VI, IX, X, and XI) although these results are unlikely to be related also play important structural and functional to the primary genetic defect in this form of roles. The normal supramolecular assembly of OA. A second type of inherited OA is familial the various cartilage collagens serves as a chondrocalcinosis-a disease in which calcium mechanical constraint to limit the expansion of pyrophosphate dihydrate (CPPD) crystals are proteoglycans and their tightly bound water on September 24, 2021 by guest. Protected copyright. deposited in fibrous and hyaline cartilage.'0 molecules into the large hydrodynamic The observations that the degenerative arthritis domains characteristic of proteoglycans in free occasionally precedes or is not associated with solution. A failure of this collagenous assembly demonstrable deposition of CPPD crystals" would result in swelling of the proteoglycans, and that there is a physical association of increased tissue water, softening of the matrix CPPD crystals with components of cartilage and eventual degeneration of the cartilage. matrix'2 13 have led to the suggestion that There is, therefore, compelling evidence to cartilage matrix abnormalities may be a suggest that cartilage collagen genes may be primary common event leading to cartilage those at fault in heritable OA. Several studies degeneration, CPPD crystal deposition, or have identified mutations in the genes both. A third familial form of OA is known as encoding type I and type III procollagens in Stickler syndrome or hereditary arthro- patients with other heritable disorders that ophthalmopathy. 4 This syndrome is cause mechanical failure of the connective Jefferson Medical characterised by ophthalmological manifesta- tissues, such as osteogenesis imperfecta.'9 College, as Thomas Jefferson tions such progressive vitreoretinal degen- These investigations have provided a number University, eration and severe myopia, peculiar facial of successful strategies for the identification of Philadelphia, features, and premature degenerative joint structural mutations in procollagen genes. PA 19107, USA disease. Other heritable S A Jimenez disorders accom- However, as discussed in more detail below, R M Dharmavaram panied by premature OA include hydroxy- many of these strategies have limitations when Correspondence to: apatite deposition disease'5 and certain forms applied to the study of mutations in the Dr S A Jimenez, of multiple epiphysial dysplasias.'6 cartilage collagen genes, such as the limited Bluemle Iife Sciences Building, The pattern of inheritance of these diseases availability of cartilage, the difficulty in 233 South 10th Street, is consistent with the hypothesis that mutations expanding chondrocyte populations in vitro, Rm 509, Philadelphia, in one or more of the genes encoding the the loss of chondrocyte-specific phenotype PA 19107-5541, USA. macromolecular components of articular during culture, and the difficulty in performing 79070imenez, Dharmavaram extensive protein characterisation from small expression of hereditary arthro-ophthal- tissue samples. The following sections will mopathy or Stickler syndrome. In the study by Ann Rheum Dis: first published as 10.1136/ard.53.12.789 on 1 December 1994. Downloaded from review some of the strategies that have been Knowlton et al,29 three large Stickler syndrome successfully utilised or that may be potentially families were analysed for co-inheritance of the useful to identify collagen gene mutations in clinical manifestations with the Hind-III and inherited diseases affecting articular cartilage. the variable number tandem repeat (VNTR) polymorphisms in COL2A1. Genetic linkage between the disease phenotype and COL2A1 Restriction fragment length was demonstrated in the largest family. The polymorphism (RFLP) analysis results from the second family also supported The development of recombinant probes that linkage to COL2A1, leading to the conclusion detect polymorphic sites in human DNA by that mutations in the COL2A1 gene are RFLP analysis has made available a vast responsible for the disease in these two resource of genetic markers to follow the families. In conrast, in the third family, re- inheritance of specific DNA sequences in combination between clinical expression and families.20'22 These polymorphic sequences COL2A1 was demonstrated suggesting, there- occur frequently in the flanking regions ofmost fore, that the syndrome may be heterogeneous genes, as well as randomly throughout genomic and that in certain families a gene other than DNA; their detection has made it possible to COL2A1 may be the defective gene. identify abnormal alleles of many genes and to Subsequently, Knowlton et al0 dem- trace their pattern of co-segregation with a onstrated co-inheritance of a phenotype of given disease phenotype in families. The premature OA and a mild chondrodystrophy premise for RFLP study of inherited forms of with polymorphisms in the type II procollagen OA is that, despite the heterogeneity and gene. Similar results were obtained in another variability of their phenotype, they are caused family with primary generalised OA.3" by a primary genetic defect that resides at However, a large study of 61 patients with a specific chromosomal locus. The disease primary generalised OA failed to show a phenotype and the defective gene must, significant difference in the frequencies of one therefore, map to the same chromosomal or more COL2A1 alleles between affected and location as reflected by their co-segregation in control individuals.32 These results thus families. Using appropriate restriction enzymes excluded the possibility that there is a common it becomes feasible to map the inherited trait mutation at COL2A1 that is responsible for the to a region in the chromosome bracketed by disease phenotype. In a more recent study, two specific markers. Weaver et al" analysed the inheritance pattern The potential benefits of utilising RFLP of Hind-III and Hinf-I RFLPs of COL2A1 in genetic linkage analysis in heritable forms of a large five generation family with multiple human OA is that it will permit the epiphysial dysplasia (MED). The data identification of the genes at fault in these indicated that the segregation patterns of http://ard.bmj.com/ disorders. Even the finding of linked genetic COL2A1 and MED phenotype were dis- markers at some distance from the responsible cordant, with recombination observed in a gene would allow definition ofthe approximate minimum of two meioses in the portion of the chromosomal location of the abnormal gene family tested. From these results, it was and its cloning and sequencing. In addition, determined that the MED locus in this family informative RFLPs can be tested in families does not map within 2 centimorgans (cM) of suffering from diseases with similar phenotypes
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