{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T04:31:49Z","timestamp":1790829109495,"version":"4.1.0"},"reference-count":25,"publisher":"The Endocrine Society","issue":"7","license":[{"start":{"date-parts":[[2020,4,13]],"date-time":"2020-04-13T00:00:00Z","timestamp":1586736000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["DFG KU 1037\/7-1"],"award-info":[{"award-number":["DFG KU 1037\/7-1"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["DFG KU 1037\/8-1"],"award-info":[{"award-number":["DFG KU 1037\/8-1"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Bundesministerium f\u00fcr Forschung und Technik","award":["BMBF 01EO1004"],"award-info":[{"award-number":["BMBF 01EO1004"]}]},{"name":"Fonds voor Wetenschappelijk Onderzoek Vlaanderen","award":["12A3814N"],"award-info":[{"award-number":["12A3814N"]}]},{"name":"Fonds voor Wetenschappelijk Onderzoek Vlaanderen","award":["1507317N"],"award-info":[{"award-number":["1507317N"]}]},{"DOI":"10.13039\/501100007229","name":"Bijzonder Onderzoeksfonds","doi-asserted-by":"publisher","award":["BOF KP: 34417"],"award-info":[{"award-number":["BOF KP: 34417"]}],"id":[{"id":"10.13039\/501100007229","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2020,7,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Context<\/jats:title>\n                  <jats:p>C-type natriuretic peptide (CNP) is critically involved in endochondral bone growth. Variants in the genes encoding CNP or its cyclic guanosine monophosphate (cGMP)-forming receptor (natriuretic peptide receptor-B [NPR-B], gene NPR2) cause monogenic growth disorders. Here we describe a novel gain-of-function variant of NPR-B associated with tall stature and macrodactyly of the great toes (epiphyseal chondrodysplasia, Miura type).<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Design<\/jats:title>\n                  <jats:p>History and clinical characteristics of 3 family members were collected. NPR2 was selected for sequencing. Skin fibroblasts and transfected HEK-293 cells were used to compare mutant versus wild-type NPR-B activities. Homology modeling was applied to understand the molecular consequences of the variant.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>Mother\u2019s height was +2.77 standard deviation scores (SDS). The heights of her 2 daughters were +1.96 SDS at 7 years and +1.30 SDS at 4 years of age. Skeletal surveys showed macrodactyly of the great toes and pseudo-epiphyses of the mid- and proximal phalanges. Sequencing identified a novel heterozygous variant c.1444_1449delATGCTG in exon 8 of NPR2, predicted to result in deletion of 2 amino acids Met482-Leu483 within the submembrane region of NPR-B. In proband\u2019s skin fibroblasts, basal cGMP levels and CNP-stimulated cGMP production were markedly increased compared with controls. Consistently, assays with transfected HEK-293 cells showed markedly augmented baseline and ligand-dependent activity of mutant NPR-B.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>We report the second activating variant within the intracellular submembrane region of NPR-B resulting in tall stature and macrodactyly. Our functional and modeling studies suggest that this domain plays a critical role in the baseline conformation and ligand-dependent structural rearrangement of NPR-B required for cGMP production.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1210\/clinem\/dgaa190","type":"journal-article","created":{"date-parts":[[2020,4,13]],"date-time":"2020-04-13T13:45:38Z","timestamp":1586785538000},"page":"2354-2366","source":"Crossref","is-referenced-by-count":9,"title":["An Activating Deletion Variant in the Submembrane Region of Natriuretic Peptide Receptor-B Causes Tall Stature"],"prefix":"10.1210","volume":"105","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1174-7340","authenticated-orcid":false,"given":"Peter","family":"Lauffer","sequence":"first","affiliation":[{"name":"Department of Clinical G enetics, Leiden University Medical Center, ZA Leiden, the Netherlands"},{"name":"Department of Paediatric Endocrinology, Emma Children\u2019s Hospital, Amsterdam University Medical Center, AZ Amsterdam, the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erick","family":"Miranda-Laferte","sequence":"additional","affiliation":[{"name":"Institute of Physiology, University of W\u00fcrzburg, W\u00fcrzburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hermine A","family":"van Duyvenvoorde","sequence":"additional","affiliation":[{"name":"Department of Clinical G enetics, Leiden University Medical Center, ZA Leiden, the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arie","family":"van Haeringen","sequence":"additional","affiliation":[{"name":"Department of Clinical G enetics, Leiden University Medical Center, ZA Leiden, the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Franziska","family":"Werner","sequence":"additional","affiliation":[{"name":"Institute of Physiology, University of W\u00fcrzburg, W\u00fcrzburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4818-6804","authenticated-orcid":false,"given":"Eveline","family":"Boudin","sequence":"additional","affiliation":[{"name":"Centre of Medical Genetics, University of Antwerp, Edegem, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hannes","family":"Schmidt","sequence":"additional","affiliation":[{"name":"Interfaculty Institute of Biochemistry, University of T\u00fcbingen, T\u00fcbingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas D","family":"Mueller","sequence":"additional","affiliation":[{"name":"Department of Molecular Plant Physiology and Biophysics, Julius-von-Sachs-Institute, Biocenter, University of W\u00fcrzburg, W\u00fcrzburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michaela","family":"Kuhn","sequence":"additional","affiliation":[{"name":"Institute of Physiology, University of 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