{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T02:09:17Z","timestamp":1791857357757,"version":"4.3.4"},"reference-count":49,"publisher":"Oxford University Press (OUP)","issue":"6","license":[{"start":{"date-parts":[[2022,4,14]],"date-time":"2022-04-14T00:00:00Z","timestamp":1649894400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["PO1\u2010DK11794"],"award-info":[{"award-number":["PO1\u2010DK11794"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["RO1\u2010DK46718"],"award-info":[{"award-number":["RO1\u2010DK46718"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["asbmr.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["JBMR Plus"],"published-print":{"date-parts":[[2022,6]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Consistent with a vital role of parathyroid hormone (PTH) receptor type 1 (PTH1R) in skeletal development, homozygous loss\u2010of\u2010function PTH1R mutations in humans results in neonatal lethality (Blomstrand chondrodysplasia), whereas such heterozygous mutations cause a primary failure of tooth eruption (PFE). Despite a key role of PTH1R in calcium and phosphate homeostasis, blood mineral ion levels are not altered in such cases of PFE. Recently, two nonlethal homozygous PTH1R mutations were identified in two unrelated families in which affected members exhibit either dental and skeletal abnormalities (PTH1R\u2010V204E) or hypocalcemia and hyperphosphatemia (PTH1R\u2010R186H). Arg186 and Val204 map to the first transmembrane helix of the PTH1R, and thus to a critical region of this class B G protein\u2010coupled receptor. We used cell\u2010based assays and PTH and PTH\u2010related protein (PTHrP) ligand analogs to assess the impact of the R186H and V204E mutations on PTH1R function in vitro. In transiently transfected HEK293 cells, PTH1R\u2010R186H mediated cyclic adenosine monophosphate (cAMP) responses to PTH(1\u201034) and PTHrP(1\u201036) that were of comparable potency to those observed on wild\u2010type PTH1R (PTH1R\u2010WT) (half maximal effective concentrations [EC50s]\u00a0=\u00a00.4nM to 1.2nM), whereas the response\u2010maxima were significantly reduced for the PTH1R\u2010V204E mutant (maximum effect [Emax]\u00a0=\u00a081%\u201377% of PTH1R\u2010WT,\n                    <jats:italic>p\u2009\u2264<\/jats:italic>\n                    \u00a00.004). Antibody binding to an extracellular hemagglutinin (HA) tag was comparable for PTH1R\u2010R186H and PTH1R\u2010WT, but was significantly reduced for PTH1R\u2010V204E (maximum binding level [Bmax]\u00a0=\u00a044%\u2009\u00b1\u200911% of PTH1R\u2010WT,\n                    <jats:italic>p<\/jats:italic>\n                    \u00a0=\u00a00.002). The potency of cAMP signaling induced by a PTH(1\u201011) analog was reduced by ninefold and threefold, respectively, for PTH1R\u2010R186H and PTH1R\u2010V204E, relative to PTH1R\u2010WT, and a PTH(1\u201015) radioligand analog that bound adequately to PTH1R\u2010WT exhibited little or no specific binding to either mutant receptor. The data support a general decrease in PTH1R surface expression and\/or function as a mechanism for PFE and a selective impairment in PTH ligand affinity as a potential PTH1R\u2010mutation\u2010based mechanism for pseudohypoparathyroidism. \u00a9 2022 The Authors.\n                    <jats:italic>JBMR Plus<\/jats:italic>\n                    published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.\n                  <\/jats:p>","DOI":"10.1002\/jbm4.10604","type":"journal-article","created":{"date-parts":[[2022,1,19]],"date-time":"2022-01-19T10:33:34Z","timestamp":1642588414000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Functional Properties of Two Distinct PTH1R Mutants Associated With Either Skeletal Defects or Pseudohypoparathyroidism"],"prefix":"10.1093","volume":"6","author":[{"given":"Ignacio","family":"Portales\u2010Castillo","sequence":"first","affiliation":[{"name":"Department of Medicine, Division of Nephrology Massachusetts General Hospital, and Harvard Medical School  Boston MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Dean","sequence":"additional","affiliation":[{"name":"Endocrine Unit Massachusetts General Hospital, and Harvard Medical School  Boston MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ashok","family":"Khatri","sequence":"additional","affiliation":[{"name":"Endocrine Unit Massachusetts General Hospital, and Harvard Medical School  Boston MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harald","family":"J\u00fcppner","sequence":"additional","affiliation":[{"name":"Endocrine Unit Massachusetts General Hospital, and Harvard Medical School  Boston MA USA"},{"name":"Pediatric Nephrology Unit Massachusetts General Hospital, and Harvard Medical School  Boston MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2163-5772","authenticated-orcid":false,"given":"Thomas J","family":"Gardella","sequence":"additional","affiliation":[{"name":"Endocrine Unit Massachusetts General Hospital, and Harvard Medical School  Boston MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2022,4,14]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddi001"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2006-0300"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI2918"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1210\/en.139.12.5255"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1007\/PL00008195"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1210\/jcem.83.9.5245"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.273.5275.663"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2008.11.006"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0167033"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00784-013-1014-3"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0074601"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1002\/jbmr.385"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.95.20.11846"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1210\/jc.86.4.1788"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms11277"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41574-021-00488-z"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1111\/cge.13601"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1111\/cge.13413"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1111\/gbb.12308"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1210\/clinem\/dgab060"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.archoralbio.2016.03.012"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.274.45.31955"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.aav7942"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41594-018-0151-4"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(18)55477-6"},{"key":"e_1_2_9_27_1","doi-asserted-by":"publisher","DOI":"10.1002\/anie.201207603"},{"key":"e_1_2_9_28_1","doi-asserted-by":"publisher","DOI":"10.1210\/me.2005-0349"},{"key":"e_1_2_9_29_1","doi-asserted-by":"publisher","DOI":"10.1210\/me.9.10.1269"},{"key":"e_1_2_9_30_1","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.91079"},{"key":"e_1_2_9_31_1","doi-asserted-by":"publisher","DOI":"10.1002\/jbm4.10441"},{"key":"e_1_2_9_32_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-15884-8"},{"key":"e_1_2_9_33_1","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.2089"},{"key":"e_1_2_9_34_1","doi-asserted-by":"publisher","DOI":"10.1210\/me.2014-1129"},{"key":"e_1_2_9_35_1","doi-asserted-by":"publisher","DOI":"10.1210\/me.2013-1314"},{"key":"e_1_2_9_36_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1205756110"},{"key":"e_1_2_9_37_1","doi-asserted-by":"publisher","DOI":"10.1210\/en.2009-1494"},{"key":"e_1_2_9_38_1","doi-asserted-by":"publisher","DOI":"10.1210\/en.2015-1726"},{"key":"e_1_2_9_39_1","doi-asserted-by":"publisher","DOI":"10.1210\/me.2005-0349"},{"key":"e_1_2_9_40_1","doi-asserted-by":"publisher","DOI":"10.1196\/annals.1346.002"},{"key":"e_1_2_9_41_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1534-5807(02)00218-6"},{"key":"e_1_2_9_42_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature01657"},{"key":"e_1_2_9_43_1","doi-asserted-by":"publisher","DOI":"10.1210\/endocr\/bqaa216"},{"key":"e_1_2_9_44_1","doi-asserted-by":"publisher","DOI":"10.1210\/mend.12.11.0198"},{"key":"e_1_2_9_45_1","doi-asserted-by":"publisher","DOI":"10.1002\/jbmr.2532"},{"key":"e_1_2_9_46_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1814670116"},{"key":"e_1_2_9_47_1","doi-asserted-by":"publisher","DOI":"10.1051\/mbcb\/2015052"},{"key":"e_1_2_9_48_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2010.01.023"},{"key":"e_1_2_9_49_1","doi-asserted-by":"publisher","DOI":"10.1210\/clinem\/dgaa279"},{"key":"e_1_2_9_50_1","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2018-00332"}],"container-title":["JBMR 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