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. Epub 2022 Jan 23.

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.

Publication types

  • Case Reports

MeSH terms

  • Adolescent
  • Adult
  • Amino Acid Sequence
  • Animals
  • Arcuate Nucleus of Hypothalamus / metabolism
  • Basic Helix-Loop-Helix Transcription Factors / chemistry
  • Basic Helix-Loop-Helix Transcription Factors / genetics*
  • Basic Helix-Loop-Helix Transcription Factors / metabolism*
  • Female
  • Genetic Variation
  • Humans
  • Hypogonadism / etiology
  • Hypogonadism / genetics*
  • Hypogonadism / metabolism
  • Kisspeptins / genetics
  • Male
  • Metabolic Networks and Pathways / genetics
  • Mice
  • Models, Molecular
  • Mutant Proteins / chemistry
  • Mutant Proteins / genetics
  • Mutant Proteins / metabolism
  • Mutation, Missense
  • Obesity / etiology
  • Obesity / genetics*
  • Obesity / metabolism
  • Pedigree
  • Promoter Regions, Genetic
  • Protein Conformation
  • Transcriptional Activation
  • Young Adult

Substances

  • Basic Helix-Loop-Helix Transcription Factors
  • KISS1 protein, human
  • Kisspeptins
  • Mutant Proteins
  • NHLH2 protein, human

Supplementary concepts

  • Idiopathic Hypogonadotropic Hypogonadism