• PMID: 25248098
• Gene Name: DMXL2
• Condition: Male infertility
• Association: Associated
• Sex: Male
• Infertility type: Male infertility

Haploinsufficiency of Dmxl2, encoding a synaptic protein, causes infertility associated with a loss of GnRH neurons in mouse

Tata B, Huijbregts L, Jacquier S, Csaba Z, Genin E, Meyer V, Leka S, Dupont J, Charles P, Chevenne D, Carel JC, Léger J, de Roux N.

Characterization of the genetic defects causing gonadotropic deficiency has made a major contribution to elucidation of the fundamental role of Kisspeptins and Neurokinin B in puberty onset and reproduction. The absence of puberty may also reveal neurodevelopmental disorders caused by molecular defects in various cellular pathways. Investigations of these neurodevelopmental disorders may provide information about the neuronal processes controlling puberty onset and reproductive capacity. We describe here a new syndrome observed in three brothers, which involves gonadotropic axis deficiency, central hypothyroidism, peripheral demyelinating sensorimotor polyneuropathy, mental retardation, and profound hypoglycemia, progressing to nonautoimmune insulin-dependent diabetes mellitus. High-throughput sequencing revealed a homozygous in-frame deletion of 15 nucleotides in DMXL2 in all three affected patients. This homozygous deletion was associated with lower DMXL2 mRNA levels in the blood lymphocytes of the patients. DMXL2 encodes the synaptic protein rabconnectin-3α, which has been identified as a putative scaffold protein for Rab3-GAP and Rab3-GEP, two regulators of the GTPase Rab3a. We found that rabconnectin-3α was expressed in exocytosis vesicles in gonadotropin-releasing hormone (GnRH) axonal extremities in the median eminence of the hypothalamus. It was also specifically expressed in cells expressing luteinizing hormone (LH) and follicle-stimulating hormone (FSH) within the pituitary. The conditional heterozygous deletion of Dmxl2 from mouse neurons delayed puberty and resulted in very low fertility. This reproductive phenotype was associated with a lower number of GnRH neurons in the hypothalamus of adult mice. Finally, Dmxl2 knockdown in an insulin-secreting cell line showed that rabconnectin-3α controlled the constitutive and glucose-induced secretion of insulin. In conclusion, this study shows that low levels of DMXL2 expression cause a complex neurological phenotype, with abnormal glucose metabolism and gonadotropic axis deficiency due to a loss of GnRH neurons. Our findings identify rabconectin-3α as a key controller of neuronal and endocrine homeostatic processes. FAU - Tata, Brooke AU - Tata B AD - Inserm, U1141, Paris, France; Université Paris Diderot, Sorbonne Paris Cité, Hôpital Robert Debré, Paris, France. FAU - Huijbregts, Lukas AU - Huijbregts L AD - Inserm, U1141, Paris, France; Université Paris Diderot, Sorbonne Paris Cité, Hôpital Robert Debré, Paris, France. FAU - Jacquier, Sandrine AU - Jacquier S AD - Inserm, U1141, Paris, France. FAU - Csaba, Zsolt AU - Csaba Z AD - Inserm, U1141, Paris, France. FAU - Genin, Emmanuelle AU - Genin E AD - Inserm, U1078, Brest, France. FAU - Meyer, Vincent AU - Meyer V AD - Genoscope, IG-DSV-CEA, Evry, France. FAU - Leka, Sofia AU - Leka S AD - Inserm, U1141, Paris, France. FAU - Dupont, Joelle AU - Dupont J AD - INRA, UMR85 Physiologie de la Reproduction et des Comportements, Nouzilly, France. FAU - Charles, Perrine AU - Charles P AD - Genetics Department and Inserm US975, Université Pierre et Marie Curie, Hôpital la Pitié-Salpêtrière, Paris, France. FAU - Chevenne, Didier AU - Chevenne D AD - AP-HP, Laboratoire de Biochimie, Hôpital Robert Debré, Paris, France. FAU - Carel, Jean-Claude AU - Carel JC AD - Inserm, U1141, Paris, France; Université Paris Diderot, Sorbonne Paris Cité, Hôpital Robert Debré, Paris, France; AP-HP, Service d'Endocrinologie Diabétologie Pédiatrique et Centre de Référence des Maladies Endocriniennes Rares de la Croissance, Hôpital Robert Debré, Paris, France. FAU - Léger, Juliane AU - Léger J AD - Inserm, U1141, Paris, France; Université Paris Diderot, Sorbonne Paris Cité, Hôpital Robert Debré, Paris, France; AP-HP, Service d'Endocrinologie Diabétologie Pédiatrique et Centre de Référence des Maladies Endocriniennes Rares de la Croissance, Hôpital Robert Debré, Paris, France.