kiss1-protein--human and Kallmann-Syndrome

The complex organization and regulation of the human hypothalamic-pituitary-gonadal axis render it susceptible to dysfunction in the face of a variety of genetic insults, leading to different degrees of hypogonadotrophic hypogonadism (HH). Although the genetic basis of some HH was recognized more than 60 years ago the first specific pathogenic defect, in the KAL1 gene, was only identified within the last 20 years. In the past decade, the rate of genetic discovery has dramatically accelerated, with defects in more than 10 genes now associated with HH. Several themes have emerged as the genetic basis of HH has gradually been uncovered, including the association of some genes such as FGFR1, FGF8, PROK2 and PROKR2, both with HH in association with hyposmia/anosmia (Kallmann syndrome) and with normosmic HH, thus blurring the clinical distinction between ontogenic and purely functional defects in the axis. Many examples of digenic inheritance of HH have also been reported, sometimes producing variable reproductive and accessory phenotypes within a family with non-Mendelian inheritance patterns. In strictly normosmic HH, human genetics has made a particularly dramatic impact in the past 6 years through homozygosity mapping in consanguineous families, first through identification of a key role for kisspeptin in triggering GnRH release, and very recently through demonstration of a critical role for neurokinin B in normal sexual maturation. This review summarises current understanding of the genetic architecture of HH, as well as its diagnostic and mechanistic implications.

Topics: Consanguinity; Extracellular Matrix Proteins; Female; Fibroblast Growth Factor 8; Gastrointestinal Hormones; Gonads; Humans; Hypogonadism; Hypothalamo-Hypophyseal System; Kallmann Syndrome; Kisspeptins; Male; Nerve Tissue Proteins; Neurokinin B; Neuropeptides; Phenotype; Receptor, Fibroblast Growth Factor, Type 1; Receptors, G-Protein-Coupled; Receptors, Kisspeptin-1; Receptors, Neurokinin-3; Receptors, Peptide; Sexual Maturation; Tumor Suppressor Proteins

Neurons that synthesize and secrete the decapeptide gonadotropin-releasing hormone-1 (GnRH-1) to control the reproductive axis originate in the olfactory placode/vomeronasal organ of the olfactory system of mammals and migrate along vomeronasal nerves to the cribriform plate, which marks the boundary between the peripheral olfactory system and the forebrain. Migrating GnRH-1 neurons follow a branch of the vomeronasal nerve caudally into the hypothalamus, where they extend processes to the median eminence and halt their migration. The release of GnRH-1 into the capillaries of the median eminence starts the cascade that activates pituitary gonadotropin (luteinizing hormone and follicle-stimulating hormone) production and secretion. Failure of these neurons to complete their migration results in failure of the reproductive axis. In some cases, failed migration is linked to the loss of the sense of smell (anosmia). The mechanisms that regulate migration of GnRH-1 neurons along this complex pathway are incompletely understood. Recent studies have revealed an important role for a series of strategically located soluble factors that regulate different aspects of GnRH-1 neuron migration at specific locations along their migratory route. This review focuses on the different mechanisms used by these factors to regulate migration of GnRH-1 neurons.

Topics: Animals; Cell Movement; Chemokine CXCL12; Chemokines, CXC; Gonadotropin-Releasing Hormone; Humans; Hypogonadism; Hypothalamo-Hypophyseal System; Kallmann Syndrome; Kisspeptins; Nerve Growth Factors; Netrin-1; Neurons; Olfactory Pathways; Prosencephalon; Protein Precursors; Receptors, CXCR4; Receptors, G-Protein-Coupled; Receptors, Kisspeptin-1; Reproduction; Signal Transduction; Tumor Suppressor Proteins

Puberty is controlled by genetic and environmental factors. This review examines the genetic basis for puberty by evaluating known gene mutations associated with disordered puberty in humans. At present, at least 17 different single-gene mutations are recognized as being associated with delayed or absent puberty in humans. Several of these genes are involved in the development of the olfactory nervous system, with mutations typically resulting in anosmia/hyposmia and hypogonadotropic hypogonadism, otherwise known as Kallmann syndrome. The biological basis for the association between smell and fertility is strong as development of the gonadotropin-releasing hormone (GnRH) neurons, responsible for regulating fertility, is intricately associated with development of the olfactory system. Other gene mutations, including the recently discovered kisspeptin-GPR54 signalling system, affect puberty by directly or indirectly modulating the functioning of the GnRH neurons and pituitary gonadotrophs. Together, these single-gene mutations are presently estimated to account for approximately 30% of individuals with disorders of puberty.. A large number of different genes are involved in the complex process of bringing about reproductive competency. In addition to the genetic mutations associated with precocious and delayed puberty, the oligogenic aetiology of these conditions is being increasingly appreciated.

Topics: Brain; Child Development; Embryonic Development; Humans; Hypogonadism; Infant; Kallmann Syndrome; Kisspeptins; Mutation; Puberty; Puberty, Delayed; Puberty, Precocious; Tumor Suppressor Proteins

Isolated hypogonadotropic hypogonadism (IHH) is characterized by complete or partial failure of pubertal development due to impaired secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH). In the molecular pathogenesis of IHH, the gonadotropin-releasing hormone receptor (GnRH-R) and associated proteins have evolved as a central element. GnRH-R germline mutations were among the first genetic alterations identified in patients with IHH. These mutations are associated with impaired GnRH binding, ligand-induced signal transduction, or both, leading to various degrees of LH and FSH deficiency. As GnRH-R mutations explain several but not all cases of IHH, the search for new candidate genes continued in informative families. In 2003, mutations of the KiSS-1-derived peptide receptor GPR54 were identified in patients with IHH, opening a new pathway in the physiologic regulation of puberty and reproduction. GPR54 is putatively involved in the control of GnRH secretion. IHH associated with impaired olfactory function (Kallmann syndrome) may be caused by mutations of the X-chromosomal KAL1 (encoding anosmin) or the fibroblast growth factor receptor 1 genes (FGFR1), both leading to agenesis of olfactory and GnRH-secreting neurons. In addition to their clinical and diagnostic value, the identification of genetic and functional alterations in IHH helps to unravel the complex regulation of the gonadotropic axis.

Topics: Extracellular Matrix Proteins; Follicle Stimulating Hormone; Germ-Line Mutation; Gonadotropin-Releasing Hormone; Gonadotropins; Humans; Hypogonadism; Kallmann Syndrome; Kisspeptins; Luteinizing Hormone; Nerve Tissue Proteins; Proteins; Receptor Protein-Tyrosine Kinases; Receptor, Fibroblast Growth Factor, Type 1; Receptors, Fibroblast Growth Factor; Receptors, G-Protein-Coupled; Receptors, Kisspeptin-1; Receptors, LHRH; Receptors, Neuropeptide; Tumor Suppressor Proteins

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 i

Topics: Amino Acid Sequence; Animals; Cell Movement; Consanguinity; Extracellular Matrix Proteins; Female; Genetic Heterogeneity; Genotype; Gonadotropin-Releasing Hormone; Humans; Hypogonadism; Hypothalamus; Kallmann Syndrome; Kisspeptins; Male; Mice; Models, Biological; Molecular Sequence Data; Nerve Tissue Proteins; Olfaction Disorders; Phenotype; Point Mutation; Proteins; Receptor Protein-Tyrosine Kinases; Receptor, Fibroblast Growth Factor, Type 1; Receptors, Fibroblast Growth Factor; Receptors, G-Protein-Coupled; Receptors, Kisspeptin-1; Receptors, LHRH; Receptors, Neuropeptide; Tumor Suppressor Proteins

Hypogonadotropic hypogonadism (HH) is hypogonadism due to either hypothalamic or pituitary dysfunction. While gonadotropin-releasing hormone (GnRH) can directly test pituitary function, no specific test of hypothalamic function exists. Kisspeptin-54 (KP54) is a neuropeptide that directly stimulates hypothalamic GnRH release and thus could be used to specifically interrogate hypothalamic function. Congenital HH (CHH) is typically due to variants in genes that control hypothalamic GnRH neuronal migration or function. Thus, we investigated whether KP54 could accurately identify hypothalamic dysfunction in men with CHH.. Men with CHH (n = 21) and healthy eugonadal men (n = 21) received an intravenous bolus of either GnRH (100 μg) or KP54 (6.4 nmol/kg), on 2 occasions, and were monitored for 6 h after administration of each neuropeptide.. Maximal luteinizing hormone (LH) rise after KP54 was significantly greater in healthy men (12.5 iU/L) than in men with CHH (0.4 iU/L; p < 0.0001). KP54 more accurately differentiated CHH men from healthy men than GnRH (area under receiver operating characteristic curve KP54: 1.0, 95% CI 1.0-1.0; GnRH: 0.88, 95% CI 0.76-0.99). Indeed, all CHH men had an LH rise <2.0 iU/L following KP54, whereas all healthy men had an LH rise >4.0 iU/L. Anosmic men with CHH (i.e., Kallmann syndrome) had even lower LH rises after KP54 than did normosmic men with CHH (p = 0.017). Likewise, men identified to have pathogenic/likely pathogenic variants in CHH genes had even lower LH rises after KP54 than other men with CHH (p = 0.035).. KP54 fully discriminated men with CHH from healthy men. Thus, KP54 could be used to specifically interrogate hypothalamic GnRH neuronal function in patients with CHH.

Topics: Adult; Gonadotropin-Releasing Hormone; Humans; Hypogonadism; Kallmann Syndrome; Kisspeptins; Luteinizing Hormone; Male

The hypothalamic hormone kisspeptin (metastin) regulates human reproduction by modulating gonadotropin-releasing hormone (GnRH) secretion. Kisspeptin is detected in peripheral blood, although GnRH is not. In this study, we measured plasma kisspeptin levels in four male cases with hypogonadism and seven normal male controls using enzyme immunoassay (EIA) to elucidate the clinical implications of kisspeptin levels in male hypogonadism. The results showed a variety of plasma kisspeptin levels: 6.0 fmol/mL in a male with isolated hypogonadotropic hypogonadism (IHH), 43.2 fmol/mL in a male with Kallmann's syndrome, 40.7 fmol/mL in a male with azoospermia, 323.2 fmol/mL in a male with hypergonadotropic hypogonadism, and 12.3 ± 2.5 fmol/mL (mean ± SD) in seven normal controls. Except for the case with IHH, the plasma kisspetin levels were elevated in the three cases with Kallmann's syndrome, azoospermia, and hypergonadotropic hypogonadism. The reason why the three cases had high values was their lesions were downstream of the kisspeptin neuron in the hypothalamic-pituitary-gonadal axis, suggesting that elevated kisspeptin levels were implicated in hypothalamic kisspeptin secretion under decreased negative feedback of gonadal steroids. The result that the plasma kisspeptin levels were decreased by gonadotropin therapy in the case with Kallmann's syndrome supported this hypothesis. In conclusion, to measure plasma kisspeptin levels could be useful for better understanding of male hypogonadism.

Topics: Adult; Azoospermia; Humans; Hypogonadism; Kallmann Syndrome; Kisspeptins; Male

Topics: Administration, Cutaneous; Estradiol; Female; Humans; Hypogonadism; Kallmann Syndrome; Kisspeptins; Puberty; Tumor Suppressor Proteins; Turner Syndrome