{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T05:55:53Z","timestamp":1791006953639,"version":"4.1.0"},"reference-count":41,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2005,4,7]],"date-time":"2005-04-07T00:00:00Z","timestamp":1112832000000},"content-version":"vor","delay-in-days":6,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Arthritis &amp; Rheumatism"],"published-print":{"date-parts":[[2005,4]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Objective<\/jats:title><jats:p>Certain mutations in <jats:italic>ANKH<\/jats:italic>, which encodes a multiple\u2010pass transmembrane protein that regulates inorganic pyrophosphate (PPi) transport, are linked to autosomal\u2010dominant familial chondrocalcinosis. This study investigated the potential for <jats:italic>ANKH<\/jats:italic> sequence variants to promote sporadic chondrocalcinosis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p><jats:italic>ANKH<\/jats:italic> variants identified by genomic sequencing were screened for association with chondrocalcinosis in 128 patients with severe sporadic chondrocalcinosis or pseudogout and in ethnically matched healthy controls. The effects of specific variants on expression of common markers were evaluated by in vitro transcription\/translation. The function of these variants was studied in transfected human immortalized CH\u20108 articular chondrocytes.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Sporadic chondrocalcinosis was associated with a G\u2010to\u2010A transition in the <jats:italic>ANKH<\/jats:italic> 5\u2032\u2010untranslated region (5\u2032\u2010UTR) at 4 bp upstream of the start codon (in homozygotes of the minor allele, genotype relative risk 6.0, <jats:italic>P<\/jats:italic> = 0.0006; overall genotype association <jats:italic>P<\/jats:italic> = 0.02). This \u22124\u2010bp transition, as well as 2 mutations previously linked with familial and sporadic chondrocalcinosis (+14 bp C\u2010to\u2010T and C\u2010terminal GAG deletion, respectively), but not the French familial chondrocalcinosis kindred 143\u2010bp T\u2010to\u2010C mutation, increased reticulocyte <jats:italic>ANKH<\/jats:italic> transcription\/ANKH translation in vitro. Transfection of complementary DNA for both the wild\u2010type ANKH and the \u22124\u2010bp ANKH protein variant promoted increased extracellular PPi in CH\u20108 cells, but unexpectedly, these ANKH mutants had divergent effects on the expression of extracellular PPi and the chondrocyte hypertrophy marker, type X collagen.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>A subset of sporadic chondrocalcinosis appears to be heritable via a \u22124\u2010bp G\u2010to\u2010A <jats:italic>ANKH<\/jats:italic> 5\u2032\u2010UTR transition that up\u2010regulates expression of ANKH and extracellular PPi in chondrocyte cells. Distinct <jats:italic>ANKH<\/jats:italic> mutations associated with heritable chondrocalcinosis may promote disease by divergent effects on extracellular PPi and chondrocyte hypertrophy, which is likely to mediate differences in the clinical phenotypes and severity of the disease.<\/jats:p><\/jats:sec>","DOI":"10.1002\/art.20978","type":"journal-article","created":{"date-parts":[[2005,4,7]],"date-time":"2005-04-07T15:23:37Z","timestamp":1112887417000},"page":"1110-1117","source":"Crossref","is-referenced-by-count":78,"title":["Association of sporadic chondrocalcinosis with a \u22124\u2010basepair G\u2010to\u2010A transition in the 5\u2032\u2010untranslated region of <i>ANKH<\/i> that promotes enhanced expression of ANKH protein and excess generation of extracellular inorganic pyrophosphate"],"prefix":"10.1002","volume":"52","author":[{"given":"Yun","family":"Zhang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristen","family":"Johnson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R. Graham G.","family":"Russell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"B. Paul","family":"Wordsworth","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew J.","family":"Carr","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert A.","family":"Terkeltaub","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew A.","family":"Brown","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2005,4,7]]},"reference":[{"key":"e_1_2_6_2_2","first-page":"411","article-title":"What does cartilage calcification tell us about osteoarthritis?","volume":"29","author":"Terkeltaub R","year":"2002","journal-title":"J Rheumatol"},{"key":"e_1_2_6_3_2","first-page":"518","article-title":"Elevated inorganic pyrophosphate concentrations in synovial fluids in osteoarthritis and pseudogout","volume":"83","author":"Silcox 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