{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,3]],"date-time":"2026-03-03T22:52:35Z","timestamp":1772578355515,"version":"3.50.1"},"reference-count":44,"publisher":"Oxford University Press (OUP)","issue":"5","content-domain":{"domain":["eje.bioscientifica.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2016,11]]},"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Homozygous inactivating mutations of the calcium-sensing receptor (<jats:italic>CaSR<\/jats:italic>) lead to neonatal severe hyperparathyroidism (NSHPT), whereas heterozygous inactivating mutations result in familial hypocalciuric hypercalcemia (FHH). It is unknown why in some cases heterozygous<jats:italic>CaSR<\/jats:italic>mutations cause neonatal hyperparathyroidism (NHPT) clinically similar to NSHPT but with only moderately elevated serum calcium.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>A literature survey was conducted to identify patients with heterozygous<jats:italic>CaSR<\/jats:italic>mutations and NHPT. The common NHPT CaSR mutants R185Q and R227L were compared with 15 mutants causing only FHH in the heterozygous state. We studied<jats:italic>in vitro<\/jats:italic>calcium signaling including the functional consequences of co-expression of mutant and wild-type (wt) CaSR, patients\u2019 phenotype, age of disease manifestation and mode of inheritance.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>All inactivating CaSR mutants impaired calcium signaling of wt-CaSR regardless of the patients\u2019 clinical phenotype. The absolute intracellular calcium signaling response to physiologic extracellular calcium concentrations<jats:italic>in vitro<\/jats:italic>showed a high correlation with patients\u2019 serum calcium concentrations<jats:italic>in vivo<\/jats:italic>, which is similar in NHPT and FHH patients with the same genotype. Pedigrees of FHH families revealed that paternal inheritance<jats:italic>per se<\/jats:italic>does not necessarily lead to NHPT but may only cause FHH.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>There is a significant correlation between<jats:italic>in vitro<\/jats:italic>functional impairment of the CaSR at physiologic calcium concentrations and the severity of alterations in calcium homeostasis in patients. Whether a particular genotype leads to NHPT or FHH appears to depend on additional predisposing genetic or environmental factors. An individual therapeutic approach appears to be warranted for NHPT patients.<\/jats:p><\/jats:sec>","DOI":"10.1530\/eje-16-0223","type":"journal-article","created":{"date-parts":[[2016,9,26]],"date-time":"2016-09-26T00:18:14Z","timestamp":1474849094000},"page":"421-431","update-policy":"https:\/\/doi.org\/10.1530\/crossmarkpolicy-1","source":"Crossref","is-referenced-by-count":30,"title":["Heterozygous inactivating CaSR mutations causing neonatal hyperparathyroidism: function, inheritance and phenotype"],"prefix":"10.1093","volume":"175","author":[{"given":"Markus","family":"Glaudo","sequence":"first","affiliation":[{"name":"1Division of Endocrinology and DiabetesDepartment of Medicine I, Universit\u00e4tsklinikum Erlangen, Erlangen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Saskia","family":"Letz","sequence":"additional","affiliation":[{"name":"1Division of Endocrinology and DiabetesDepartment of Medicine I, Universit\u00e4tsklinikum Erlangen, Erlangen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marcus","family":"Quinkler","sequence":"additional","affiliation":[{"name":"2Endokrinologie in CharlottenburgBerlin, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ulrich","family":"Bogner","sequence":"additional","affiliation":[{"name":"2Endokrinologie in CharlottenburgBerlin, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ulf","family":"Elbelt","sequence":"additional","affiliation":[{"name":"3Department of EndocrinologyDiabetes and Nutrition"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christian J","family":"Strasburger","sequence":"additional","affiliation":[{"name":"3Department of EndocrinologyDiabetes and Nutrition"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dirk","family":"Schnabel","sequence":"additional","affiliation":[{"name":"4Center for Chronic Sick ChildrenPediatric Endocrinology and Diabetes, Charit\u00e9 \u2013 Universit\u00e4tsmedizin Berlin, Berlin, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Erwin","family":"Lankes","sequence":"additional","affiliation":[{"name":"4Center for Chronic Sick ChildrenPediatric Endocrinology and Diabetes, Charit\u00e9 \u2013 Universit\u00e4tsmedizin Berlin, Berlin, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sandra","family":"Scheel","sequence":"additional","affiliation":[{"name":"5Endocrinology and DiabetologyKlinikum Bielefeld, Bielefeld, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joachim","family":"Feldkamp","sequence":"additional","affiliation":[{"name":"5Endocrinology and DiabetologyKlinikum Bielefeld, Bielefeld, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christine","family":"Haag","sequence":"additional","affiliation":[{"name":"6Endocrine PracticeHeidelberg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Egbert","family":"Schulze","sequence":"additional","affiliation":[{"name":"6Endocrine PracticeHeidelberg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Karin","family":"Frank-Raue","sequence":"additional","affiliation":[{"name":"6Endocrine PracticeHeidelberg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Friedhelm","family":"Raue","sequence":"additional","affiliation":[{"name":"6Endocrine PracticeHeidelberg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bernhard","family":"Mayr","sequence":"additional","affiliation":[{"name":"1Division of Endocrinology and DiabetesDepartment of Medicine I, Universit\u00e4tsklinikum Erlangen, Erlangen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christof","family":"Sch\u00f6fl","sequence":"additional","affiliation":[{"name":"1Division of Endocrinology and DiabetesDepartment of Medicine I, Universit\u00e4tsklinikum Erlangen, Erlangen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","reference":[{"key":"2016092517180941000_175.5.421.1","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1016\/j.berh.2007.11.006","article-title":"Hypercalcaemic and hypocalcaemic conditions due to calcium-sensing receptor mutations","volume":"22","author":"Egbuna","year":"2008","journal-title":"Best Practice & Research. 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