{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,27]],"date-time":"2026-03-27T21:10:44Z","timestamp":1774645844745,"version":"3.50.1"},"reference-count":27,"publisher":"Oxford University Press (OUP)","issue":"1","content-domain":{"domain":["eje.bioscientifica.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2013,7]]},"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>Loss-of-function calcium-sensing receptor (<jats:italic>CAR<\/jats:italic>) mutations cause elevated parathyroid hormone (PTH) secretion and hypercalcaemia. Although full <jats:italic>Car<\/jats:italic> deletion is possible in mice, most human <jats:italic>CAR<\/jats:italic> mutations result from a single amino acid substitution that maintains partial function. However, here, we report a case of neonatal severe hyperparathyroidism (NSHPT) in which the truncated <jats:italic>CaR<\/jats:italic> lacks any transmembrane domain (CaR<jats:sup>R392X<\/jats:sup>), in effect a full <jats:italic>CAR<\/jats:italic> \u2018knockout\u2019.<\/jats:p><\/jats:sec><jats:sec><jats:title>Case report<\/jats:title><jats:p>The infant (daughter of distant cousins) presented with hypercalcaemia (5.5\u20136\u200ammol\/l corrected calcium (2.15\u20132.65)) and elevated PTH concentrations (650\u2013950\u200apmol\/l (12\u201381)) together with skeletal demineralisation. NSHPT was confirmed by <jats:italic>CAR<\/jats:italic> gene sequencing (homozygous c.1174C-to-T mutation) requiring total parathyroidectomy during which only two glands were located and removed, resulting in normalisation of her serum PTH\/calcium levels.<\/jats:p><\/jats:sec><jats:sec><jats:title>Design and methods<\/jats:title><jats:p>The R392X stop codon was inserted into human CAR and the resulting mutant (CaR<jats:sup>R392X<\/jats:sup>) expressed transiently in HEK-293 cells.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>CaR<jats:sup>R392X<\/jats:sup> expressed as a 54\u200akDa dimeric glycoprotein that was undetectable in conditioned medium or in the patient's urine. The membrane localisation observed for wild-type CaR in parathyroid gland and transfected HEK-293 cells was absent from the proband's parathyroid gland and from CaR<jats:sup>R392X<\/jats:sup>-transfected cells. Expression of the mutant was localised to endoplasmic reticulum consistent with its lack of functional activity.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Intriguingly, the patient remained normocalcaemic throughout childhood (2.5\u200amM corrected calcium, 11\u200apg\/ml PTH (10\u201371), age 8 years) but exhibited mild asymptomatic hypocalcaemia at age 10 years, now treated with 1-hydroxycholecalciferol and Ca<jats:sup>2<\/jats:sup><jats:sup>+<\/jats:sup> supplementation. Despite representing a virtual <jats:italic>CAR<\/jats:italic> knockout, the patient displays no obvious pathologies beyond her calcium homeostatic dysfunction.<\/jats:p><\/jats:sec>","DOI":"10.1530\/eje-13-0094","type":"journal-article","created":{"date-parts":[[2013,4,24]],"date-time":"2013-04-24T03:55:40Z","timestamp":1366775740000},"page":"K1-K7","update-policy":"https:\/\/doi.org\/10.1530\/crossmarkpolicy-1","source":"Crossref","is-referenced-by-count":9,"title":["Molecular and clinical analysis of a neonatal severe hyperparathyroidism case caused by a stop mutation in the calcium-sensing receptor extracellular domain representing in effect a human \u2018knockout\u2019"],"prefix":"10.1093","volume":"169","author":[{"given":"D T","family":"Ward","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"M Z","family":"Mughal","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"M","family":"Ranieri","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"M M","family":"Dvorak-Ewell","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"G","family":"Valenti","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"D","family":"Riccardi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","reference":[{"key":"1_39237574","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1016\/S1877-1173(09)89003-0","volume":"89","year":"2009","journal-title":"PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE"},{"issue":"3","key":"2_18225398","doi-asserted-by":"publisher","first-page":"275","DOI":"10.1016\/j.ceca.2003.10.010","volume":"35","author":"Thakker","year":"2004","journal-title":"Cell calcium","ISSN":"https:\/\/id.crossref.org\/issn\/0143-4160","issn-type":"print"},{"issue":"12","key":"3_42391911","doi-asserted-by":"publisher","first-page":"943","DOI":"10.1016\/j.clinbiochem.2012.03.034","volume":"45","author":"Ward","year":"2012","journal-title":"Clinical biochemistry","ISSN":"https:\/\/id.crossref.org\/issn\/0009-9120","issn-type":"print"},{"issue":"3","key":"4_29287460","doi-asserted-by":"publisher","first-page":"385","DOI":"10.1111\/j.1365-2265.2007.02896.x","volume":"67","author":"Toke","year":"2007","journal-title":"Clinical endocrinology","ISSN":"https:\/\/id.crossref.org\/issn\/0300-0664","issn-type":"print"},{"issue":"12","key":"5_42148637","doi-asserted-by":"publisher","first-page":"2768","DOI":"10.1093\/hmg\/dds105","volume":"21","year":"2012","journal-title":"Human Molecular Genetics","ISSN":"https:\/\/id.crossref.org\/issn\/0964-6906","issn-type":"print"},{"issue":"35","key":"6_31788271","doi-asserted-by":"publisher","first-page":"ra1","DOI":"10.1126\/scisignal.1159945","volume":"1","author":"Chang","year":"2008","journal-title":"Science Signaling","ISSN":"https:\/\/id.crossref.org\/issn\/1945-0877","issn-type":"print"},{"issue":"11","key":"7_43679192","doi-asserted-by":"publisher","first-page":"1879","DOI":"10.1681\/ASN.2012030323","volume":"23","year":"2012","journal-title":"Journal of the American Society of Nephrology","ISSN":"https:\/\/id.crossref.org\/issn\/1046-6673","issn-type":"print"},{"issue":"5","key":"8_38392339","doi-asserted-by":"publisher","first-page":"625","DOI":"10.1007\/s00431-010-1335-z","volume":"170","author":"Al-Khalaf","year":"2011","journal-title":"European journal of pediatrics","ISSN":"https:\/\/id.crossref.org\/issn\/0340-6199","issn-type":"print"},{"issue":"8","key":"9_16873766","doi-asserted-by":"publisher","first-page":"2716","DOI":"10.1210\/jc.82.8.2716","volume":"82","author":"Kobayashi","year":"1997","journal-title":"Journal of Clinical Endocrinology &amp; 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