Neuron-Derived Neurotrophic Factor Is Mutated in Congenital Hypogonadotropic Hypogonadism.
Details
Serval ID
serval:BIB_42DF4A84796E
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Neuron-Derived Neurotrophic Factor Is Mutated in Congenital Hypogonadotropic Hypogonadism.
Journal
American journal of human genetics
ISSN
1537-6605 (Electronic)
ISSN-L
0002-9297
Publication state
Published
Issued date
02/01/2020
Peer-reviewed
Oui
Volume
106
Number
1
Pages
58-70
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Publication Status: ppublish
Abstract
Congenital hypogonadotropic hypogonadism (CHH) is a rare genetic disorder characterized by infertility and the absence of puberty. Defects in GnRH neuron migration or altered GnRH secretion and/or action lead to a severe gonadotropin-releasing hormone (GnRH) deficiency. Given the close developmental association of GnRH neurons with the olfactory primary axons, CHH is often associated with anosmia or hyposmia, in which case it is defined as Kallmann syndrome (KS). The genetics of CHH are heterogeneous, and >40 genes are involved either alone or in combination. Several CHH-related genes controlling GnRH ontogeny encode proteins containing fibronectin-3 (FN3) domains, which are important for brain and neural development. Therefore, we hypothesized that defects in other FN3-superfamily genes would underlie CHH. Next-generation sequencing was performed for 240 CHH unrelated probands and filtered for rare, protein-truncating variants (PTVs) in FN3-superfamily genes. Compared to gnomAD controls the CHH cohort was statistically enriched for PTVs in neuron-derived neurotrophic factor (NDNF) (p = 1.40 × 10 <sup>-6</sup> ). Three heterozygous PTVs (p.Lys62 <sup>∗</sup> , p.Tyr128Thrfs <sup>∗</sup> 55, and p.Trp469 <sup>∗</sup> , all absent from the gnomAD database) and an additional heterozygous missense mutation (p.Thr201Ser) were found in four KS probands. Notably, NDNF is expressed along the GnRH neuron migratory route in both mouse embryos and human fetuses and enhances GnRH neuron migration. Further, knock down of the zebrafish ortholog of NDNF resulted in altered GnRH migration. Finally, mice lacking Ndnf showed delayed GnRH neuron migration and altered olfactory axonal projections to the olfactory bulb; both results are consistent with a role of NDNF in GnRH neuron development. Altogether, our results highlight NDNF as a gene involved in the GnRH neuron migration implicated in KS.
Keywords
Adolescent, Animals, Cell Movement, Cohort Studies, Female, Heterozygote, Humans, Hypogonadism/congenital, Hypogonadism/genetics, Hypogonadism/pathology, Male, Mice, Mice, Knockout, Mutation, Nerve Growth Factors/genetics, Nerve Growth Factors/physiology, Neurons/metabolism, Neurons/pathology, Pedigree, Zebrafish
Pubmed
Web of science
Create date
03/01/2020 22:36
Last modification date
27/04/2020 6:20