title: [GnRH deficiency: new insights from genetics].
abstract: The acquisition of a sexually dimorphic phenotype is a critical event in mammalian development. Hypogonadotropic hypogonadism (HH) results from impaired secretion of GnRH. The patients display with delayed puberty, micropenis and cryptorchidism in the male reflecting gonadotropin insufficiency, and amenorrhea in the female. Kallmann's syndrome (KS) is defined by the association of HH and anosmia or hyposmia (absent smelling sense). Segregation analysis in familial cases has demonstrated diverse inheritance patterns, suggesting the existence of several genes regulating GnRH secretion. The X-linked form of the disease was associated with a genetic defect in the KALI gene located on the Xp22.3 region. KAL1 gene encodes an extracellular matrix glycoprotein anosmin-1, which facilitates neuronal growth and migration. Abnormalities in the migratory processes of the GnRH neurons with the olfactory neurons explain the association of HH with anosmia. Recently, mutations in the FGF recepteur 1 (FGFR1) gene were found in KS with autosomal dominant mode of inheritance. The role of FGFR1 in the function of reproduction requires further investigation. Besides HH with anosmia, there are isolated HH (IHH). No human GnRH mutations have been reported although hypogonadal mice due to a GnRH gene deletion exist. In patients with idiopathic HH and without anosmia an increasing number of GnRH receptor (GnRHR) mutations have been described which represent about 50% of familial cases. The clinical features are highly variable and there is a good relationship between genotype and phenotype. A complete loss of function is associated with the most severe phenotype with resistance to pulsatile GnRH treatment, absence of puberty and cryptorchidism in the male. In contrast, milder loss of function mutations causes incomplete failure of pubertal development. The preponderant role of GnRH in the secretion of LH by the gonadotrophs explains the difference of the phenotype between male and female with partial GnRH resistance. Affected females can have spontaneous telarche and normal breast development while affected males exhibit no pubertal development but normal testis volume, a feature described as "fertile-eunuch". High-dose pulsatile GnRH has been used to induce ovulation. Another gene, called GPR54, responsible for idiopathic HH has been recently described by segregation analysis in two different consanguineous families. The GPR54 gene is an orphan receptor, and its putative ligand is the product of the KISS-1 gene, called metastine. Their roles in the function of reproduction are still unknown.
authors.affiliation: Département Génétique et Reproduction, Unité de génétique moléculaire, CHU de Caen, Avenue Georges Clemenceau, 14033 Caen. kottler-ml@chu-caen.fr
authors.forename: Marie-Laure
authors.initials: ML
authors.lastname: Kottler
authors.forename: Adèle
authors.initials: A
authors.lastname: Hamel
authors.forename: Elodie
authors.initials: E
authors.lastname: Malville
authors.forename: Nicolas
authors.initials: N
authors.lastname: Richard
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002465:Cell Movement; D003241:Consanguinity; D016326:Extracellular Matrix Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D005260:Female; D018740:Genetic Heterogeneity; D005838:Genotype; D007987:Gonadotropin-Releasing Hormone / Q000172:deficiency* / Q000502:physiology; D006801:Humans; D007006:Hypogonadism / Q000235:genetics* / Q000503:physiopathology; D007031:Hypothalamus / Q000166:cytology / Q000196:embryology; D017436:Kallmann Syndrome / Q000235:genetics / Q000503:physiopathology; D059648:Kisspeptins; D008297:Male; D051379:Mice; D008954:Models, Biological; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D000857:Olfaction Disorders / Q000150:complications / Q000235:genetics; D010641:Phenotype; D017354:Point Mutation; D011506:Proteins / Q000502:physiology; D020794:Receptor Protein-Tyrosine Kinases / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D051496:Receptor, Fibroblast Growth Factor, Type 1; D017468:Receptors, Fibroblast Growth Factor / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D043562:Receptors, G-Protein-Coupled; D000074502:Receptors, Kisspeptin-1; D011966:Receptors, LHRH / Q000737:chemistry / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D018013:Receptors, Neuropeptide / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D025521:Tumor Suppressor Proteins
chemical_list: C076266:ANOS1 protein, human; D016326:Extracellular Matrix Proteins; C484844:GNRHR protein, human; C106628:KISS1 protein, human; C118688:KISS1R protein, human; C491407:Kiss1 protein, mouse; C492248:Kiss1r protein, mouse; D059648:Kisspeptins; D009419:Nerve Tissue Proteins; D011506:Proteins; D017468:Receptors, Fibroblast Growth Factor; D043562:Receptors, G-Protein-Coupled; D000074502:Receptors, Kisspeptin-1; D011966:Receptors, LHRH; D018013:Receptors, Neuropeptide; D025521:Tumor Suppressor Proteins; D007987:Gonadotropin-Releasing Hormone; C496348:FGFR1 protein, human; C496349:Fgfr1 protein, mouse; D020794:Receptor Protein-Tyrosine Kinases; D051496:Receptor, Fibroblast Growth Factor, Type 1