ESPEYB17 7. Puberty Basic Science (8 abstracts)
7.11. Neuron-derived neurotrophic factor is mutated in congenital hypogonadotropic hypogonadism
Messina A , Pulli K , Santini S , Acierno J , Känsäkoski J , Cassatella D , Xu C , Casoni F , Malone SA , Ternier G , Conte D , Sidis Y , Tommiska J , Vaaralahti K , Dwyer A , Gothilf Y , Merlo GR , Santoni F , Niederländer NJ , Giacobini P , Raivio T & Pitteloud N
To read the full abstract: American journal of human genetics vol. 106,1 (2020): 58–70. doi: https://www.sciencedirect.com/science/article/pii/S0002929719304677?via%3Dihub
By performing next-generation sequencing in 240 unrelated probands with congenital hypogonadotropic hypogonadism and follow-up in multiple animal models, this study identifies Neuron-Derived Neurotrophic Factor as a gene involved in GnRH neuron migration and implicated in Kallmann syndrome.
Congenital hypogonadotropic hypogonadism (CHH) is a rare genetic disorder caused by absent secretion or action of gonadotropin-releasing hormone (GnRH) and is characterized by infertility and the absence of puberty (1). CHH associated with anosmia defines Kallmann syndrome (KS). CHH is a complex genetic disorder for which more than 40 causal genes have been identified, each accounting for fewer than 10% of cases (2). Fifty percent of subjects with CHH do not carry mutations in the known CHH-associated genes. Previous next-generation sequencing studies for CHH included small population size and limited ability to detect statistically significant associations with variants at most known CHH-causing genes.
Here, the authors studied 240 unrelated CHH probands (140 KS and 100 normosmic CHH). They used an analysis strategy to combine collapsed gene-based burden testing with targeting of genes in the FN3 superfamily. Several proteins involved in GnRH neuron migration, and previously implicated in CHH, contain FN3 domains. Using this strategy, they identified an enrichment for protein-truncating variants in Neuron-Derived Neurotrophic Factor (NDNF), which encodes a secreted glycosylated disulfide-bond protein containing FN3 domains. Overall, ˜3% of individuals with KS harbour NDNF mutations. In addition, authors showed that NDNF is expressed in the nasal region after formation of the olfactory placode in mice and humans. Knockdown of the ortholog of NDNF in zebrafish resulted in altered GnRH migration, and mice lacking NDNF showed delayed GnRH neuron migration and altered olfactory axonal projections to the olfactory bulb.
Together, these results provide strong evidence for a role of NDNF in GnRH neuron migration. Further investigations are needed to identify the molecular signalling pathway used by NDNF in GnRH neuron ontogeny, and to dissect the contribution of genetic and environmental factors potentially modifying the phenotype of subjects carrying NDNF loss-of-function mutations.
References:
1. Young J, Xu C, Papadakis GE, Acierno JS, Maione L, Hietama ?ki J, Raivio T, Pitteloud N. (2019). Clinical management of congenital hypogonadotropic hypogonadism. Endocr. Rev. 40, 669–710.
2. Cassatella D, Howard SR, Acierno JS, Xu C, Papadakis GE, Santoni FA, Dwyer AA, Santini S, Sykiotis GP, Chambion C, et al. (2018). Congenital hypogonadotropic hypogonadism and constitutional delay of growth and puberty have distinct genetic architectures. European J. Endocri- nol. 178, 377–388.
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ESPE Yearbook of Paediatric Endocrinology
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