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Yet, gain of function variants in the melanocortin-4-receptor (\n                    <jats:italic>MC4R<\/jats:italic>\n                    ) gene predispose to a lower BMI. In individuals with reduced body weight, we thus expected mutations leading to an enhanced function in the respective genes, like leptin (\n                    <jats:italic>LEP)<\/jats:italic>\n                    and\n                    <jats:italic>MC4R<\/jats:italic>\n                    . Therefore, we have Sanger sequenced the coding regions of\n                    <jats:italic>LEP<\/jats:italic>\n                    and\n                    <jats:italic>MC4R<\/jats:italic>\n                    in 462 female patients with anorexia nervosa (AN), and 445 healthy-lean controls. In total, we have observed four and eight variants in\n                    <jats:italic>LEP<\/jats:italic>\n                    and\n                    <jats:italic>MC4R<\/jats:italic>\n                    , respectively. Previous studies showed different functional in vitro effects for the detected frameshift and non-synonymous variants: (1)\n                    <jats:italic>LEP<\/jats:italic>\n                    : reduced\/loss of function (p.Val94Met), (2)\n                    <jats:italic>MC4R<\/jats:italic>\n                    : gain of function (p.Val103Ile, p.Ile251Leu), reduced or loss of function (p.Thr112Met, p.Ser127Leu, p.Leu211\n                    <jats:italic>fs<\/jats:italic>\n                    X) and without functional in vitro data (p.Val50Leut). In\n                    <jats:italic>LEP<\/jats:italic>\n                    , the variant p.Val94Met was detected in one patient with AN. For\n                    <jats:italic>MC4R<\/jats:italic>\n                    variants, one patient with AN carried the frameshift variant p.Leu211\n                    <jats:italic>fs<\/jats:italic>\n                    X. One patient with AN was heterozygous for two variants at the\n                    <jats:italic>MC4R<\/jats:italic>\n                    (p.Val103Ile and p.Ser127Leu). All other functionally relevant variants were detected in similar frequencies in patients with AN and lean individuals.\n                  <\/jats:p>","DOI":"10.1038\/s41598-024-57517-w","type":"journal-article","created":{"date-parts":[[2024,3,25]],"date-time":"2024-03-25T17:40:27Z","timestamp":1711388427000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Unexpected identification of obesity-associated mutations in LEP and MC4R genes in patients with anorexia nervosa"],"prefix":"10.1038","volume":"14","author":[{"given":"Luisa Sophie","family":"Rajcsanyi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiran","family":"Zheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beate","family":"Herpertz-Dahlmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jochen","family":"Seitz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martina","family":"de Zwaan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wolfgang","family":"Herzog","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan","family":"Ehrlich","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephan","family":"Zipfel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katrin","family":"Giel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karin","family":"Egberts","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roland","family":"Burghardt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manuel","family":"F\u00f6cker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jochen","family":"Antel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pamela","family":"Fischer-Posovszky","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johannes","family":"Hebebrand","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anke","family":"Hinney","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,3,25]]},"reference":[{"key":"57517_CR1","doi-asserted-by":"publisher","DOI":"10.1176\/appi.books.9780890425596","volume-title":"Diagnostic and Statistical Manual of Mental Disorders (DSM-5\u00ae)","author":"Association, A. 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