{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,25]],"date-time":"2026-07-25T14:19:09Z","timestamp":1784989149214,"version":"3.55.0"},"reference-count":47,"publisher":"Oxford University Press (OUP)","issue":"4","license":[{"start":{"date-parts":[[2024,3,30]],"date-time":"2024-03-30T00:00:00Z","timestamp":1711756800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,3,30]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Purpose<\/jats:title>\n                  <jats:p>The purpose of this study was to characterize the phenotype associated with a de novo gain-of-function variant in the GUCY1A2 gene.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>An individual carrying the de novo heterozygous variant c.1458G&amp;gt;T p.(E486D) in GUCY1A2 was identified by exome sequencing. The effect of the corresponding enzyme variant \u03b12E486D\/\u03b21 was evaluated using concentration-response measurements with wild-type enzyme and the variant in cytosolic fractions of HEK293 cells, UV-vis absorbance spectra of the corresponding purified enzymes, and examination of overexpressed fluorescent protein-tagged constructs by confocal laser scanning microscopy.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>The patient presented with precocious peripheral puberty resembling the autonomous ovarian puberty seen in McCune-Albright syndrome. Additionally, the patient displayed severe intellectual disability. In vitro activity assays revealed an increased nitric oxide affinity for the mutant enzyme. The response to carbon monoxide was unchanged, while thermostability was decreased compared to wild type. Heme content, susceptibility to oxidation, and subcellular localization upon overexpression were unchanged.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>Our data define a syndromic autonomous ovarian puberty likely due to the activating allele p.(E486D) in GUCY1A2 leading to an increase in cGMP. The overlap with the ovarian symptoms of McCune-Albright syndrome suggests an impact of this cGMP increase on the cAMP pathway in the ovary. Additional cases will be needed to ensure a causal link.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/ejendo\/lvae030","type":"journal-article","created":{"date-parts":[[2024,4,5]],"date-time":"2024-04-05T15:45:52Z","timestamp":1712331952000},"page":"266-274","source":"Crossref","is-referenced-by-count":2,"title":["Heterozygous gain of function variant in <i>GUCY1A2<\/i> may cause autonomous ovarian hyperfunction"],"prefix":"10.1093","volume":"190","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0911-4376","authenticated-orcid":false,"given":"Theresa","family":"Wittrien","sequence":"first","affiliation":[{"name":"Department of Pharmacology, Toxicology and Clinical Pharmacy, University of Braunschweig\u2014Institute of Technology , 38106 Braunschweig , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alban","family":"Ziegler","sequence":"additional","affiliation":[{"name":"Department of Genetics, University Hospital of Angers , 49933 Angers , 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