2. Academic Validation
  3. Inactivating NHLH2 variants cause idiopathic hypogonadotropic hypogonadism and obesity in humans

Inactivating NHLH2 variants cause idiopathic hypogonadotropic hypogonadism and obesity in humans

  • Hum Genet. 2022 Feb;141(2):295-304. doi: 10.1007/s00439-021-02422-9.
A Kemal Topaloglu 1 2,  Enver Simsek 3,  Matthew A Kocher 4,  Jamala Mammadova 5,  Ece Bober 6,  Leman Damla Kotan 7,  Ihsan Turan 7,  Can Celiloglu 7,  Fatih Gurbuz 7,  Bilgin Yuksel 7,  Deborah J Good 4 8
Affiliations

Affiliations

  • 1 Department of Pediatrics, Division of Pediatric Endocrinology, University of Mississippi Medical Center, Jackson, MS, USA. ktopaloglu@umc.edu.
  • 2 Department of Neurobiology and Anatomical Sciences, University of Mississippi Medical Center, Jackson, MS, USA. ktopaloglu@umc.edu.
  • 3 Division of Pediatric Endocrinology, Faculty of Medicine, Eskisehir Osman Gazi University, Eskisehir, Turkey.
  • 4 Translational Biology, Medicine and Health Graduate Program, Virginia Tech, Roanoke, VA, USA.
  • 5 Division of Pediatric Endocrinology, Faculty of Medicine, Ondokuz Mayis University, Samsun, Turkey.
  • 6 Division of Pediatric Endocrinology, Faculty of Medicine, Dokuz Eylul University, Izmir, Turkey.
  • 7 Division of Pediatric Endocrinology, Faculty of Medicine, Cukurova University, Adana, Turkey.
  • 8 Department of Human Nutrition, Foods, and Exercise, Virginia Tech, Blacksburg, VA, USA.
PMID: 35066646 DOI: 10.1007/s00439-021-02422-9
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 nucleus of the hypothalamus constitute the GnRH (gonadotropin-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 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 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.

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