RESUMEN
The olfacto-genital syndrome (Kallmann syndrome) associates congenital hypogonadism due to gonadotropin-releasing hormone (GnRH) deficiency and anosmia. This is a genetically heterogeneous developmental disease with various modes of transmission, including oligogenic inheritance. Previous reports have involved defective cell signaling by semaphorin-3A in the disease pathogenesis. Here, we report that the embryonic phenotype of Plxna1-/- mutant mice lacking plexin-A1 (a major receptor of class 3 semaphorins), though not fully penetrant, resembles that of Kallmann syndrome fetuses. Pathohistological analysis indeed showed a strongly abnormal development of the peripheral olfactory system and defective embryonic migration of the neuroendocrine GnRH cells to the hypothalamic brain region in some of the mutant mice, which resulted in reduced fertility in adult males. We thus screened 250 patients for the presence of mutations in PLXNA1, and identified different nonsynonymous mutations (p.V349L, p.V437L, p.R528W, p.H684Y, p.G720E, p.R740H, p.R813H, p.R840Q, p.A854T, p.R897H, p.L1464V, p.K1618T, p.C1744F), all at heterozygous state, in 15 patients. Most of these mutations are predicted to affect plexin-A1 stability or signaling activity based on predictive algorithms and a structural model of the protein. Moreover, in vitro experiments allowed us to show the existence of deleterious effects of eight mutations (including a transcript splicing defect), none of which are expected to result in a complete loss of protein synthesis, targeting, or signaling activity, though. Our findings indicate that signaling insufficiency through plexin-A1 can contribute to the pathogenesis of Kallmann syndrome, and further substantiate the oligogenic pattern of inheritance in this developmental disorder.
Asunto(s)
Síndrome de Kallmann/metabolismo , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Receptores de Superficie Celular/genética , Receptores de Superficie Celular/metabolismo , Adulto , Animales , Movimiento Celular , Femenino , Hormona Liberadora de Gonadotropina/deficiencia , Heterocigoto , Humanos , Hipogonadismo/genética , Hipotálamo/metabolismo , Masculino , Ratones , Mutación , Proteínas del Tejido Nervioso/fisiología , Células Neuroendocrinas/metabolismo , Neuronas/metabolismo , Bulbo Olfatorio/fisiología , Receptores de Superficie Celular/fisiología , Reproducción , Semaforina-3A/genética , Semaforina-3A/metabolismo , Semaforinas/metabolismo , Transducción de SeñalRESUMEN
Hypothalamo-pituitary development during embryogenesis is a highly complex process involving the interaction of a network of spatiotemporally regulated signaling molecules and transcription factors. Mutations in any of the genes encoding these components can lead to congenital hypopituitarism, which is often associated with a wide spectrum of defects affecting craniofacial/midline development. In turn, these defects can be incompatible with life, or lead to disorders encompassing holoprosencephaly (HPE) and cleft palate, and septo-optic dysplasia (SOD). In recent years, there has been increasing evidence of an overlapping genotype between this spectrum of disorders and Kallmann syndrome (KS), defined as the association of hypogonadotropic hypogonadism (HH) and anosmia. This is consistent with the known phenotypic overlap between these disorders and opens a new avenue of identifying novel genetic causes of the hypopituitarism spectrum. This chapter reviews the genetic and molecular events leading to the successful development of the hypothalamo-pituitary axis during embryogenesis, and focuses on genes in which variations/mutations occur, leading to congenital hypopituitarism and associated defects.
Asunto(s)
Hipotálamo/embriología , Hipotálamo/fisiología , Hipófisis/embriología , Hipófisis/fisiología , Factores de Transcripción/genética , Animales , Genotipo , Humanos , Hipopituitarismo/genética , Hipopituitarismo/metabolismo , Sistema Hipotálamo-Hipofisario/crecimiento & desarrollo , Sistema Hipotálamo-Hipofisario/metabolismo , Síndrome de Kallmann/genética , Síndrome de Kallmann/metabolismo , Factores de Transcripción/metabolismoRESUMEN
Hypogonadotropic hypogonadism (HH) is defined by the absence of sex steroid synthesis associated with the lack of appropriate gonadotrophin secretion. This leads to a variable degree of impuberism, often diagnosed during childhood or adolescence. Genetics of HH involve many genes. However, molecular defects have been identified in only 30 % of patients. Kallmann syndrome (KS) is defined by the association of HH and anosmia. Six genes are involved in KS (KAL1, FGFR1, FGF8, PROK2, PROKR2 and CHD7). However, genetics of KS is complex, because of the variability of the phenotype for a similar molecular defect. Otherwise, heterozygous anomalies are frequently described. Identification in the same patient of several mutations in some of these genes (digenism) could account for this variability. Autosomal recessive transmission is frequently observed in familial cases of HH without anosmia. Molecular alterations have been identified for several neuropeptides or their corresponding receptors, which are involved in the physiology of the gonadotropic axis : GNRHR, KISS1R/GPR54, neurokinin B (TAC3), TACR3 and GNRH1 (and PROK2, PROKR2 and CHD7). Anomalies of leptin or its receptor are also involved in HH cases. A new negative regulating element has been recently identified in humans : RFRP3, which is ortholog of the avian GnIH (gonadotrophin inhibitory hormone). Recent progress about these neuropeptides leads to a new model of comprehension of the gonadotropic axis physiology, from a linear model to a network model, which regulates the central element of regulation of the gonadotropic axis, represented by the GnRH neurons.
Asunto(s)
Gónadas/metabolismo , Hipogonadismo/metabolismo , Hipotálamo/metabolismo , Hipófisis/metabolismo , ADN Helicasas/genética , Proteínas de Unión al ADN/genética , Proteínas de la Matriz Extracelular/genética , Femenino , Factor 8 de Crecimiento de Fibroblastos/genética , Hormonas Gastrointestinales/genética , Humanos , Hipogonadismo/genética , Síndrome de Kallmann/genética , Síndrome de Kallmann/metabolismo , Leptina/genética , Masculino , Proteínas del Tejido Nervioso/genética , Neuropéptidos/genética , Trastornos del Olfato/genética , Hormonas Inhibidoras de la Liberación de Hormona Hipofisaria/metabolismo , Receptor Tipo 1 de Factor de Crecimiento de Fibroblastos/genética , Receptores Acoplados a Proteínas G/genética , Receptores de Leptina/genética , Receptores de Péptidos/genéticaRESUMEN
Advances in our understanding of the pathophysiology of Kallmann syndrome have come from an interdisciplinary approach involving developmental biology, clinical investigation, and molecular biology. It is equally clear that progress to date is but the first chapter of what will be a fascinating biological story. It now seems likely that the full expression of reproductive potential from the neuroendocrine perspective is likely to be as complicated as other aspects of reproduction, such as the multigene control of external genital differentiation. An analogous story may well emerge for the neuroendocrine control of reproduction in which the GnRH gene is encoded on the eighth chromosome, the protein guiding the embryonic journey of the GnRH-producing neuron to the hypothalamus lies on the X chromosome, and many, as yet to be determined, other genetic loci collaborate in the full expression of reproductive potential. Such a detailed study is warranted not only because of the clinical and genetic implications for an individual patient with this disorder, but also from an organizational theme for the evolution of the species (and its potential regulation). Given the pressing nature of world population growth, obtaining such understanding and its applications to fertility and contraception is crucial. These advances will only come from enlightened interactions of clinical investigators, molecular geneticists, and developmental biologists in which interdisciplinary approaches should be fostered. This should be an exciting story to follow given the remarkable nature of the tools at hand to study these clinical conditions.