Early‐onset primary osteoarthritis and mild chondrodysplasia

Katzenstein, Paul L.; Malemud, Charles J.; Pathria, Mini N.; Carter, John R.; Sheon, Robert P.; Moskowitz, Roland W.

doi:10.1002/art.1780330510

Cited by 27 publications

(2 citation statements)

References 44 publications

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“…The family examined here developed signs and symptoms characteristic of primary generalized osteoarthritis in the second to third decades of life (5,8). Previous linkage studies on three generations of the family demonstrated that one allele for the type II procollagen gene was coinherited with the phenotype with a logarithm of the odds (lod) score of 3.56 at a recombination map distance of zero (5).…”

Section: Discussionmentioning

confidence: 96%

“…Here we have cloned the allele for type II procollagen previously shown to be coinherited with primary generalized osteoarthritis and a mild chondrodysplasia in one family (5). Affected members of the family began to develop joint pain and stiffness in the second and third decades and thereafter developed Heberden's nodes and typical radiographic evidence of osteoarthritis in hips, knees, shoulders, wrists, and hands (5,8). In addition, affected members of the family had flattening of some metatarsal heads and spinal changes consisting of irregular endplates, flattening of vertebrae, and wedge-shaped deformities indicating a mild chondrodysplasia.…”

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Single base mutation in the type II procollagen gene (COL2A1) as a cause of primary osteoarthritis associated with a mild chondrodysplasia.

Ala‐Kokko

Baldwin

Moskowitz

et al. 1990

Proc. Natl. Acad. Sci. U.S.A.

238

124

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A cosmid clone was isolated that contained an allele for the type II procollagen gene previously shown to be coinherited with primary generalized osteoarthritis in a large family. Affected members of the family had evidence of a mild chondrodysplasia, but they developed progressive osteoarthritic changes in many joints that had no epiphyseal deformities. The clone contained 52 of the 54 exons of the gene. Nucleotide sequencing of >20,000 base pairs from the clone demonstrated that all the coding sequences and all the intronexon boundaries were normal except for a single base mutation that converted the codon for arginine at position 519 of the al(ll) chain to a codon for cysteine, an amino acid not found in type II collagen from humans or a variety of other species.The mutation was found in all affected members of the family but not in unaffected members or in 57 unrelated individuals.Osteoarthritis is a common disease that produces joint pain and stiffness together with radiologic evidence of progressive degeneration of joint cartilage (1). Some forms of osteoarthritis are secondary to events such as trauma, infections, metabolic disorders, or congenital or heritable conditions that deform the epiphyses or related structures. In most patients, however, there is no readily identifiable cause of osteoarthritis. At the same time, inheritance in a Mendelian dominant manner has been demonstrated in some families with primary generalized osteoarthritis, the idiopathic form of the disease characterized by the appearance of osteophytes around the distal joints of the fingers (Heberden's nodes) and progressive degeneration of cartilage in the knees, hips, and most otherjoints (2, 3). Two recent reports on three unrelated families (4, 5) demonstrated coinheritance of primary generalized osteoarthritis with specific alleles of the gene for type II procollagen (COL2AI ), the precursor of the major protein of cartilage (6, 7). Here we have cloned the allele for type II procollagen previously shown to be coinherited with primary generalized osteoarthritis and a mild chondrodysplasia in one family (5). Affected members of the family began to develop joint pain and stiffness in the second and third decades and thereafter developed Heberden's nodes and typical radiographic evidence of osteoarthritis in hips, knees, shoulders, wrists, and hands (5, 8). In addition, affected members of the family had flattening of some metatarsal heads and spinal changes consisting of irregular endplates, flattening of vertebrae, and wedge-shaped deformities indicating a mild chondrodysplasia. The osteoarthritic changes, however, developed progressively in many joints that did not have any epiphyseal deformities or other evidence of a chondrodysplasia. Common causes of secondary osteoarthritis were excluded and the disease was best classified as primary generalized osteoarthritis associated with a mild chondrodysplasia. Here, we demonstrate that the allele linked to the disease had a single base mutation that converted the codon for argin...

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Section: Discussionmentioning

confidence: 96%

mentioning

confidence: 99%

Single base mutation in the type II procollagen gene (COL2A1) as a cause of primary osteoarthritis associated with a mild chondrodysplasia.

Ala‐Kokko

Baldwin

Moskowitz

et al. 1990

Proc. Natl. Acad. Sci. U.S.A.

238

124

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Phenotypic expressions of a Gly154Arg mutation in type II collagen in two unrelated patients with spondyloepimetaphyseal dysplasia (SEMD)

et al. 1996

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Type II collagenopathies consist of chondrodysplasias ranging from lethal to mild in severity. A large number of mutations has been found in the COL2A1 gene. Glycine substitutions have been the most common types of mutation. Genotype‐phenotype correlations in type II collagenopathies have not been established, partly because of insufficient clinical and radiographic description of the patients. We found a glycine‐to‐arginine substitution at position 154 in type II collagen in two unrelated isolated propositi with spondyloepimetaphyseal dysplasia and provide a comparative clinical and radiographic analysis from birth to young adulthood for this condition. The clinical phenotype was disproportionate short stature with varus/valgus deformities of the lower limbs requiring corrective osteotomies, and lumbar lordosis. The skeletal radiographs showed an evolution from short tubular bones, delayed epiphyseal development, and mild vertebral involvement to severe metaphyseal dysplasia with dappling irregularities, and hip “dysplasia.” The metaphyseal abnormalities disappeared by adulthood. © 1996 Wiley‐Liss, Inc.

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Changes in serum cartilage marker levels indicate altered cartilage metabolism in families with the osteoarthritis-related type II collagen gene COL2A1 mutation

Bleasel

Poole

Heinegård

et al. 1999

Arthritis & Rheumatism

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Study of the macromolecular constituents of cartilage released into serum in subjects with familial OA revealed altered metabolism in OA, as demonstrated by elevated COMP and KS levels. Other constituents, the 846 epitope and CPII, were not altered, indicating dissociation of cartilage anabolism and breakdown. Future sequential studies will provide an opportunity to define biochemical changes as familial OA develops and to monitor therapeutic responses.

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Early‐onset primary osteoarthritis and mild chondrodysplasia

Cited by 27 publications

References 44 publications

Single base mutation in the type II procollagen gene (COL2A1) as a cause of primary osteoarthritis associated with a mild chondrodysplasia.

Single base mutation in the type II procollagen gene (COL2A1) as a cause of primary osteoarthritis associated with a mild chondrodysplasia.

Phenotypic expressions of a Gly154Arg mutation in type II collagen in two unrelated patients with spondyloepimetaphyseal dysplasia (SEMD)

Changes in serum cartilage marker levels indicate altered cartilage metabolism in families with the osteoarthritis-related type II collagen gene COL2A1 mutation

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