Puberty diseases : Genetic mechanisms and clinical implications

Specifically, we focus on the abnormal development and control of the Gonadotropin Releasing Hormone (GnRH) neuron system in the hypothalamus, responsible for the correct onset of puberty and adult fertility. An understanding of puberty initiation and its impairment, by the characterization of this relatively simple neuronal network and the mechanisms that control it, should help to decipher other mechanisms involved in the development of NDDs in general.

  Our research consists of two main and complementary axes.

1. Role of Rbcn-3α in the development and maturation of GnRH neurons

  We have shown that the haploinsufficiency of DMXL2, which encodes the synaptic protein Rabconnectin-3α (Rbcn-3α), causes:

1. an absence of puberty;
2. intellectual disability;
3. proprioceptive ataxia;
4. a demyelinating polyneuropathy;
5. other endocrine deficiencies.

  The investigation of Dmxl2 deficiency in mouse brains has revealed that the pubertal dysfunction is due to the impairment of the morphological and functional maturation of GnRH neurons, itself caused by a membrane trafficking defect in afferent neurons (Tata B. et al., PLoS Biol 2014) (Tata B.K. et al., Sci Rep 2017).

2. Characterization of new proteins that participate in the timing of GnRH neuronal maturation

  We have also characterized or contributed to the characterization of other mutations involved in abnormal pubertal onset, including several loss-of-function mutations in MKRN3 (a suspected negative regulator of GnRH neuronal maturation) (Simon D. et al., Eur J Endocrinol 2016), involved in familial forms of central precocious puberty (CPP).
CPP is caused by an acceleration of the maturation of the GnRH neuronal network. The identification of new genes linked to CPP is useful not only to characterize the cellular functions involved in the maturation of the GnRH network, but also to investigate the role of these proteins in cellular ageing or the development of certain benign tumors.
With this objective in mind, we will develop an ambitious human genetics program to characterize genes linked to isolated CPP and subsequently study the molecular mechanisms by which the newly identified proteins control the timing of GnRH neuronal maturation.