{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T15:28:09Z","timestamp":1784820489281,"version":"3.55.0"},"reference-count":34,"publisher":"The Endocrine Society","issue":"5","license":[{"start":{"date-parts":[[2025,11,21]],"date-time":"2025-11-21T00:00:00Z","timestamp":1763683200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/501100001677","name":"Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001677","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Paris-Saclay University"},{"DOI":"10.13039\/501100008979","name":"Soci\u00e9t\u00e9 Fran\u00e7aise d\u2019Endocrinologie","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100008979","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,4,22]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Context<\/jats:title>\n                    <jats:p>Hypogonadotropic hypogonadism (HH) with severe ataxia, impotence, and dementia has been reported in a handful of patients carrying RNF216 gene variants. However, the underlying molecular mechanism explaining this complex phenotype remains unclear to date. RNF216 encodes a \u201cRING-between-RING\u201d(RBR)-class E3 ubiquitin ligase. Among the targets of RNF216 is Beclin-1, a pivotal regulator of autophagy, particularly within the central nervous system.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objectives<\/jats:title>\n                    <jats:p>(i) To assess the prevalence of RN216 mutations in a large cohort of patients with HH. (ii) To examine the impact on autophagy of identified RNF216 pathogenic variants.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Exome analysis in a monocentric cohort of patients with HH. In vitro functional analysis of RNF216 variants in the regulation of autophagy and cell viability.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Among 1476 patients, we identified a unique NM_207111.4:c.2056C&amp;gt;T:p.(Arg686*) RNF216 variant in the homozygous state in one family with 2 affected patients presenting with HH associated with late-onset ataxia and dementia. We observed that in cells expressing this RNF216 variant, the regulation of autophagy was disrupted, indicating a loss-of-function effect. We demonstrated that inhibiting RNF216 expression decreased cell viability. Z-VAD, a pan-caspase inhibitor, did not protect cells from death, whereas 3-MA, an autophagy inhibitor, prevented cell death. Interestingly, we found that other RNF216 variants reported to be associated with this form of HH had a similar functional impact on autophagy.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Our results suggest that alteration of RNF216 function leads to cell death through an autophagy-mediated mechanism which contributes to combined HH and ataxia and dementia in affected patients.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1210\/clinem\/dgaf640","type":"journal-article","created":{"date-parts":[[2025,11,20]],"date-time":"2025-11-20T13:37:09Z","timestamp":1763645829000},"page":"1278-1286","source":"Crossref","is-referenced-by-count":2,"title":["<i>RNF216<\/i>\n                    Variants Found in Patients With Dementia, Hypogonadotropic Hypogonadism, and Severe Ataxia Deregulate Autophagy"],"prefix":"10.1210","volume":"111","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9286-5631","authenticated-orcid":false,"given":"Jacques","family":"Young","sequence":"first","affiliation":[{"name":"Universit\u00e9 Paris-Saclay, Inserm, Physiologie et Physiopathologie Endocriniennes , Le Kremlin-Bic\u00eatre 94276, France"},{"name":"AP-HP, H\u00f4pital Bic\u00eatre, Service D'Endocrinologie et des Maladies de la Reproduction, Centre de R\u00e9f\u00e9rence des Maladies Rares de L'Hypophyse , Le Kremlin-Bic\u00eatre 94270 ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7501-287X","authenticated-orcid":false,"given":"In\u00e8s","family":"Abdennebi","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris-Saclay, Inserm, Physiologie et Physiopathologie Endocriniennes , Le Kremlin-Bic\u00eatre 94276, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marion","family":"Le Sa\u00ebc","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris-Saclay, Inserm, Physiologie et Physiopathologie Endocriniennes , Le Kremlin-Bic\u00eatre 94276, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fran\u00e7oise","family":"Magnin","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris-Saclay, Inserm, Physiologie et Physiopathologie Endocriniennes , Le Kremlin-Bic\u00eatre 94276, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Larbi","family":"Amazit","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris-Saclay, Inserm, Institut Biom\u00e9dical du Val de Bi\u00e8vre , Villejuif 94800, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1994-4226","authenticated-orcid":false,"given":"Peter","family":"Kamenick\u00fd","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris-Saclay, Inserm, Physiologie et Physiopathologie Endocriniennes , Le Kremlin-Bic\u00eatre 94276, France"},{"name":"AP-HP, H\u00f4pital Bic\u00eatre, Service D'Endocrinologie et des Maladies de la Reproduction, Centre de R\u00e9f\u00e9rence des Maladies Rares de L'Hypophyse , Le Kremlin-Bic\u00eatre 94270 ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8526-8046","authenticated-orcid":false,"given":"Luigi","family":"Maione","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris-Saclay, Inserm, Physiologie et Physiopathologie Endocriniennes , Le Kremlin-Bic\u00eatre 94276, France"},{"name":"AP-HP, H\u00f4pital Bic\u00eatre, Service D'Endocrinologie et des Maladies de la Reproduction, Centre de R\u00e9f\u00e9rence des Maladies Rares de L'Hypophyse , Le Kremlin-Bic\u00eatre 94270 ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8691-9469","authenticated-orcid":false,"given":"J\u00e9r\u00f4me","family":"Bouligand","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris-Saclay, Inserm, Physiologie et Physiopathologie Endocriniennes , Le Kremlin-Bic\u00eatre 94276, France"},{"name":"AP-HP, H\u00f4pital Bic\u00eatre, Service de G\u00e9n\u00e9tique Mol\u00e9culaire et D\u2019Hormonologie , Le Kremlin-Bic\u00eatre 94276 ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3352-6813","authenticated-orcid":false,"given":"Isabelle","family":"Beau","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris-Saclay, Inserm, Physiologie et Physiopathologie Endocriniennes , Le Kremlin-Bic\u00eatre 94276, 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