{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,15]],"date-time":"2026-07-15T09:12:30Z","timestamp":1784106750007,"version":"3.55.0"},"reference-count":75,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,3,21]],"date-time":"2022-03-21T00:00:00Z","timestamp":1647820800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003285","name":"Ministerio de Salud de la Naci\u00f3n","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100003285","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002923","name":"Consejo Nacional de Investigaciones Cient\u00edficas y T\u00e9cnicas","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100002923","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Endocrinol."],"abstract":"<jats:p>The von Hippel\u2013Lindau (VHL) disease is an autosomal dominant cancer syndrome caused by mutations in the <jats:italic>VHL<\/jats:italic> tumor suppressor gene. VHL protein (pVHL) forms a complex (VBC) with Elongins B-C, Cullin2, and Rbx1. Although other functions have been discovered, the most described function of pVHL is to recognize and target hypoxia-inducible factor (HIF) for degradation. This work comprises the functional characterization of two novel variants of the VHL gene (P138R and L163R) that have been described in our center in patients with VHL disease by <jats:italic>in vitro<\/jats:italic>, <jats:italic>in vivo<\/jats:italic>, and <jats:italic>in silico<\/jats:italic> approaches. <jats:italic>In vitro<\/jats:italic>, we found that these variants have a significantly shorter half-life compared to wild-type VHL but still form a functional VBC complex. Altered fibronectin deposition was evidenced for both variants using immunofluorescence. <jats:italic>In vivo<\/jats:italic> studies revealed that both variants failed to suppress tumor growth. By means of molecular dynamics simulations, we inspected <jats:italic>in silico<\/jats:italic> the nature of the changes introduced by each variant in the VBC complex. We have demonstrated the pathogenicity of P138R and L163R novel variants, involving HIF-dependent and HIF-independent mechanisms. These results provide the basis for future studies regarding the impact of structural alterations on posttranslational modifications that drive pVHL\u2019s fate and functions.<\/jats:p>","DOI":"10.3389\/fendo.2022.854365","type":"journal-article","created":{"date-parts":[[2022,3,23]],"date-time":"2022-03-23T03:57:21Z","timestamp":1648007841000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["VHL-P138R and VHL-L163R Novel Variants: Mechanisms of VHL Pathogenicity Involving HIF-Dependent and HIF-Independent Actions"],"prefix":"10.3389","volume":"13","author":[{"given":"Cecilia","family":"Math\u00f3","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda Celia","family":"Fern\u00e1ndez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jenner","family":"Bonanata","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xian-De","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ayelen","family":"Martin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana","family":"Vieites","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriela","family":"Sans\u00f3","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marta","family":"Barontini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric","family":"Jonasch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"E. 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