Inactivating NHLH2 Variants Cause Idiopathic Hypogonadotropic Hypogonadism and Obesity in Humans

Inactivating NHLH2 Variants Cause Idiopathic Hypogonadotropic Hypogonadism and Obesity in Humans | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Inactivating NHLH2 Variants Cause Idiopathic Hypogonadotropic Hypogonadism and Obesity in Humans A. Kemal Topaloglu, Enver Simsek, Matthew A. Kocher, Jamala Mammadova, and 7 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-1256866/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 22 Jan, 2022 Read the published version in Human Genetics → Version 1 posted You are reading this latest preprint version Abstract Metabolism has a role in determining the time of pubertal development and fertility. Nonetheless, molecular/cellular pathways linking metabolism/body weight to puberty/reproduction are unknown. The KNDy (Kisspeptin/Neurokinin B/Dynorphin) neurons in the arcuate (ARC) nucleus of the hypothalamus constitute the GnRH (Gonadotrophin-releasing hormone) pulse generator. We previously created a mouse model with a whole-body targeted deletion of nescient helix-loop-helix 2 ( Nhlh2; N2KO), a class II member of the basic helix-loop-helix (bHLH) family of transcription factors. As this mouse model features pubertal failure and late-onset obesity, we wanted to study whether NHLH2 represents a candidate molecule to link metabolism and puberty in the hypothalamus. Exome sequencing of a large Idiopathic Hypogonadotropic Hypogonadism (IHH) cohort revealed obese patients with rare sequence variants in NHLH2, which were characterized by in silico protein analysis, chromatin immunoprecipitation, and luciferase reporter assays. In vitro heterologous expression studies demonstrated that the variant p.R79C impairs Nhlh2 binding to the Mc4r promoter. Furthermore, p.R79C and other variants show impaired transactivation of the human KISS1 promoter. These are the first inactivating human variants that support NHLH2’s critical role in human puberty and body weight control. Failure to carry out this function results in the absence of pubertal development and late-onset obesity in humans. NHLH2 Idiopathic Hypogonadotropic Hypogonadism Obesity Kisspeptin MC4R Full Text Cite Share Download PDF Status: Published Journal Publication published 22 Jan, 2022 Read the published version in Human Genetics → Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-1256866","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":76324539,"identity":"b58c630a-18e2-45ec-bb45-a8043456cf84","order_by":0,"name":"A. 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Nonetheless, molecular/cellular pathways linking metabolism/body weight to puberty/reproduction are unknown. The KNDy (Kisspeptin/Neurokinin B/Dynorphin) neurons in the arcuate (ARC) nucleus of the hypothalamus constitute the GnRH (Gonadotrophin-releasing hormone) pulse generator. We previously created a mouse model with a whole-body targeted deletion of nescient helix-loop-helix 2 (\u003cem\u003eNhlh2;\u003c/em\u003e N2KO), a class II member of the basic helix-loop-helix (bHLH) family of transcription factors. As this mouse model features pubertal failure and late-onset obesity, we wanted to study whether NHLH2 represents a candidate molecule to link metabolism and puberty in the hypothalamus. Exome sequencing of a large Idiopathic Hypogonadotropic Hypogonadism (IHH) cohort revealed obese patients with rare sequence variants in \u003cem\u003eNHLH2, \u003c/em\u003ewhich were characterized by \u003cem\u003ein silico \u003c/em\u003eprotein analysis, chromatin immunoprecipitation, and luciferase reporter assays. \u003cem\u003eIn vitro\u003c/em\u003e heterologous expression studies demonstrated that the variant p.R79C impairs Nhlh2 binding to the Mc4r promoter. Furthermore, p.R79C and other variants show impaired transactivation of the human KISS1 promoter. These are the first inactivating human variants that support \u003cem\u003eNHLH2’s \u003c/em\u003ecritical role in human puberty and body weight control. Failure to carry out this function results in the absence of pubertal development and late-onset obesity in humans.\u0026nbsp;\u003c/p\u003e\u003cp\u003e\u003cbr\u003e\u003c/p\u003e","manuscriptTitle":"Inactivating NHLH2 Variants Cause Idiopathic Hypogonadotropic Hypogonadism and Obesity in Humans","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2022-01-13 19:58:17","doi":"10.21203/rs.3.rs-1256866/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"1b6df5d7-2ce7-4091-ad99-9a8c7b2ca1c5","owner":[],"postedDate":"January 13th, 2022","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2022-01-23T00:48:44+00:00","versionOfRecord":{"articleIdentity":"rs-1256866","link":"https://doi.org/10.1007/s00439-021-02422-9","journal":{"identity":"human-genetics","isVorOnly":false,"title":"Human Genetics"},"publishedOn":"2022-01-23 00:48:44","publishedOnDateReadable":"January 23rd, 2022"},"versionCreatedAt":"2022-01-13 19:58:17","video":"","vorDoi":"10.1007/s00439-021-02422-9","vorDoiUrl":"https://doi.org/10.1007/s00439-021-02422-9","workflowStages":[]},"version":"v1","identity":"rs-1256866","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-1256866","identity":"rs-1256866","version":["v1"]},"buildId":"ApUGefWb6u5IBVtyqm6d5","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}