Osteoarthritis in Children Associated with a Mutation in the Type II Procollagen Gene (COL2A1)

Mier, Richard J.; Holderbaum, Daniel; Ferguson, Rebecca; Moskowitz, Roland W.

doi:10.1006/mgme.2001.3250

Cited by 18 publications

(13 citation statements)

References 8 publications

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“…Cleft palate can be present but hearing loss was not found in our family or previously reported patients. [11][12][13][14][15][16] Complaints of joint pain can start in childhood or early adulthood and mild spondyloepiphyseal involvement is usually found. 13 16 Osteochondritis dissecans was observed in three families.…”

Section: Discussionmentioning

confidence: 99%

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The phenotypic spectrum in patients with arginine to cysteine mutations in the COL2A1 gene

Hoornaert

Dewinter²,

Vereecke³

et al. 2005

Journal of Medical Genetics

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Section: Discussionmentioning

confidence: 99%

“…13 16 Osteochondritis dissecans was observed in three families. 14 16 17 In four families at least one patient with Perthes disease was diagnosed. 13 15 16 There is evidence for a founder effect in these reported families.…”

Section: Discussionmentioning

confidence: 99%

The phenotypic spectrum in patients with arginine to cysteine mutations in the COL2A1 gene

Hoornaert

Dewinter²,

Vereecke³

et al. 2005

Journal of Medical Genetics

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“…The substitution of arginine to cysteine at position 519 (Arg519Cys) in the procollagen gene type II α1 (proα1[II]) chain (amino acids of the α1[II] chain are numbered from the first glycine in the triple helix area) causes early generalized OA with chondrodysplasia in humans (7–11). This disease affects the hips, knees, hands, ankles, elbows, and spine, and joint pain begins to develop in patients between the ages of 5 years and 9 years (10).…”

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confidence: 99%

A human COL2A1 gene with an Arg519Cys mutation causes osteochondrodysplasia in transgenic mice

Sahlman

Pitkänen

Prockop

et al. 2004

Arthritis & Rheumatism

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Objective. An arginine-to-cysteine substitution at position 519 of the COL2A1 gene causes early generalized osteoarthritis with mild chondrodysplasia in humans. In this study, a human COL2A1 gene with the same mutation was introduced into a murine genome having 1 or no alleles of the murine Col2a1 gene, and the skeletal phenotypes of the transgenic mice were compared with those of control mice.Methods. Mice with 1 allele of the normal murine Col2a1 gene and 1 allele of the mutated human COL2A1 gene (n ‫؍‬ 10), those with no murine Col2a1 gene and 2 alleles of the mutated human COL2A1 gene (n ‫؍‬ 13), those with no murine Col2a1 gene and only 1 allele of the mutated COL2A1 gene (n ‫؍‬ 9), and normal control mice (n ‫؍‬ 11) were studied for skeletal abnormalities, using radiographic imaging and light microscopic analyses of histologic sections. The collagen network of cartilage was also investigated with transmission electron microscopy.Results. At 2 months of age, all transgenic mice had dysplastic changes in their long bones, flattened vertebral bodies, and osteoarthritic changes in their joints. The intervertebral discs of the transgenic animals were degenerated, and their histologic structure was disturbed. The changes were more severe in mice with no murine Col2a1 allele.Conclusion. The human COL2A1 gene with the Arg519Cys mutation causes osteochondrodysplasia in mice, as it does in humans.

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“…approach to a nomenclature based on divergent evolution, including number/letter/number, has been proposed for several dozen gene families and superfamilies [Nebert et al, 1987;Nelson et al, 1996;Mackenzie et al, 1997;Vasiliou et al, 1999;Nuclear Receptors Nomenclature Committee, 1999;Freimuth et al, 2000;Mier et al, 2001;Nelson, 2002;Povey et al, 2002], which has been uniformly and enthusiastically embraced by the scientific community. It should be noted that, in contrast to naming genes, the alternating use of number/letter/number/letter for designating haplotypes of genes that have diverged throughout the evolution of Homo sapiens sapiens, might possibly become strings of four or more numbers and letters each (e.g., *7A28T17L47B88), depending on the gene and especially for larger genes.…”

Section: Suggested Approachto Naming Haplotypes Based On Evolutionarymentioning

confidence: 99%

Proposal for an allele nomenclature system based on the evolutionary divergence of haplotypes

Nebert

2002

Hum. Mutat.

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The classical view of what constitutes an "allele" has been challenged by recent findings of a great deal of human genetic variability, i.e., we can expect, on average, one variant site every 100-250 bases of our haploid genome. The haplotype is defined as "the patterns of co-occurrence of variant sites on the same chromosome" (and therefore within each particular gene). Sufficient evidence exists for the divergence of haplotypes during evolution of Homo sapiens sapiens, and the total number of haplotypes per gene will reflect the amount of time any particular ethnic group has existed on the planet, e.g., greatest in Africans, fewer in East Asians, and still fewer in Caucasians. If the average gene spans 30 kb, we can expect approximately 170 polymorphic variant sites per gene in the world population. We do not see 2(170) haplotypes, however; we might find only 10 to 200 haplotypes (depending on the gene's size and degree of conservation of the gene product). This finite number allows for a reasonable haplotype nomenclature system for each gene, based on evolutionary divergence. For polymorphic variants (i.e., frequency > or = 0.01), I propose using Arabic numerals for the major clades (e.g., *1, *2, em leader *20, *21), capital letters for sublineages (e.g., *2A, *2B, *2C), and Arabic numerals for sub-sublineages (e.g., *22G12, *22G13); additional subcategories may be added, in an alternating number/letter/number/letter sequence, depending on the complexity of present-day haplotypes of a particular gene. Web sites with a web master and external advisory committee should be set up for each gene superfamily, family, or individual gene (depending on complexity), and an international haplotype nomenclature committee, perhaps comprised of several dozen of these web masters, should oversee haplotype nomenclature for the entire human genome. The higher heterozygosity and multiallelic nature makes haplotypes more informative than biallelic SNPs. Ultimately, our knowledge of haplotype patterns, rather than single variant sites, of perhaps several hundred genes will likely be helpful in finding associations between genotype and any multiplex phenotype (e.g., complex diseases including cancer, and/or toxicity of pharmaceutical agents or environmental pollutants).

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Osteoarthritis in Children Associated with a Mutation in the Type II Procollagen Gene (COL2A1)

Cited by 18 publications

References 8 publications

The phenotypic spectrum in patients with arginine to cysteine mutations in the COL2A1 gene

The phenotypic spectrum in patients with arginine to cysteine mutations in the COL2A1 gene

A human COL2A1 gene with an Arg519Cys mutation causes osteochondrodysplasia in transgenic mice

Proposal for an allele nomenclature system based on the evolutionary divergence of haplotypes

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