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1.
Growth Horm IGF Res ; 38: 14-18, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29277338

RESUMO

Several acquired or congenital hypothalamic abnormalities may cause growth failure (GF). We described two of these congenital abnormalities. First, a case of CHARGE syndrome, an epigenetic disorder mostly caused by heterozygous mutations in the gene encoding CHD7, a chromatin remodeling protein, causing several malformations, some life-threatening, with additional secondary hypothalamus-hypophyseal dysfunction, including GF. Second, a cohort of individuals with genetic isolated severe GH deficiency (IGHD), due to a homozygous mutation in the GH-releasing hormone (GHRH) receptor gene described in Itabaianinha County, in northeast Brazil. In this IGHD, with marked reduction of serum concentrations of IGF-I, and an up regulation of IGF-II, GF is the principal finding in otherwise normal subjects, with normal quality of life and longevity. This IGHD may unveil the effects of GHRH, pituitary GH and IGF-I, IGF-II and local GH and growth factor on the size and function of body and several systems. For instance, anterior pituitary hypoplasia, and impairment of the non-REM sleep may be due to GHRH resistance. Proportionate short stature, doll facies, high-pitched pre-pubertal voice, and reduced muscle mass reflect the lack of the synergistic effect of pituitary GH and IGF-I in bones and muscles. Central adiposity may be due to a direct effect of the lack of GH. Brain, eyes and immune system may also involve IGF-II and local GH or growth factors. A concept of physiological hierarchy controlling body size and function by each component of the GH system may be drawn from this model.


Assuntos
Síndrome CHARGE/etiologia , Nanismo Hipofisário/etiologia , Transtornos do Crescimento/etiologia , Hipotálamo/anormalidades , Mutação , Receptores de Neuropeptídeos/deficiência , Receptores de Hormônios Reguladores de Hormônio Hipofisário/deficiência , Adulto , Pré-Escolar , Feminino , Humanos , Masculino , Receptores de Neuropeptídeos/genética , Receptores de Hormônios Reguladores de Hormônio Hipofisário/genética
2.
J Soc Biol ; 198(1): 80-7, 2004.
Artigo em Francês | MEDLINE | ID: mdl-15146960

RESUMO

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.


Assuntos
Hormônio Liberador de Gonadotropina/deficiência , Hipogonadismo/genética , Receptores LHRH/deficiência , Sequência de Aminoácidos , Animais , Movimento Celular , Consanguinidade , Proteínas da Matriz Extracelular/deficiência , Proteínas da Matriz Extracelular/genética , Proteínas da Matriz Extracelular/fisiologia , Feminino , Heterogeneidade Genética , Genótipo , Hormônio Liberador de Gonadotropina/fisiologia , Humanos , Hipogonadismo/fisiopatologia , Hipotálamo/citologia , Hipotálamo/embriologia , Síndrome de Kallmann/genética , Síndrome de Kallmann/fisiopatologia , Kisspeptinas , Masculino , Camundongos , Modelos Biológicos , Dados de Sequência Molecular , Proteínas do Tecido Nervoso/deficiência , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/fisiologia , Transtornos do Olfato/complicações , Transtornos do Olfato/genética , Fenótipo , Mutação Puntual , Proteínas/fisiologia , Receptores Proteína Tirosina Quinases/deficiência , Receptores Proteína Tirosina Quinases/genética , Receptores Proteína Tirosina Quinases/fisiologia , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos , Receptores de Fatores de Crescimento de Fibroblastos/deficiência , Receptores de Fatores de Crescimento de Fibroblastos/genética , Receptores de Fatores de Crescimento de Fibroblastos/fisiologia , Receptores Acoplados a Proteínas G , Receptores de Kisspeptina-1 , Receptores LHRH/química , Receptores LHRH/genética , Receptores LHRH/fisiologia , Receptores de Neuropeptídeos/deficiência , Receptores de Neuropeptídeos/genética , Receptores de Neuropeptídeos/fisiologia , Proteínas Supressoras de Tumor
3.
N Engl J Med ; 349(17): 1614-27, 2003 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-14573733

RESUMO

BACKGROUND: Puberty, a complex biologic process involving sexual development, accelerated linear growth, and adrenal maturation, is initiated when gonadotropin-releasing hormone begins to be secreted by the hypothalamus. We conducted studies in humans and mice to identify the genetic factors that determine the onset of puberty. METHODS: We used complementary genetic approaches in humans and in mice. A consanguineous family with members who lacked pubertal development (idiopathic hypogonadotropic hypogonadism) was examined for mutations in a candidate gene, GPR54, which encodes a G protein-coupled receptor. Functional differences between wild-type and mutant GPR54 were examined in vitro. In parallel, a Gpr54-deficient mouse model was created and phenotyped. Responsiveness to exogenous gonadotropin-releasing hormone was assessed in both the humans and the mice. RESULTS: Affected patients in the index pedigree were homozygous for an L148S mutation in GPR54, and an unrelated proband with idiopathic hypogonadotropic hypogonadism was determined to have two separate mutations, R331X and X399R. The in vitro transfection of COS-7 cells with mutant constructs demonstrated a significantly decreased accumulation of inositol phosphate. The patient carrying the compound heterozygous mutations (R331X and X399R) had attenuated secretion of endogenous gonadotropin-releasing hormone and a left-shifted dose-response curve for gonadotropin-releasing hormone as compared with six patients who had idiopathic hypogonadotropic hypogonadism without GPR54 mutations. The Gpr54-deficient mice had isolated hypogonadotropic hypogonadism (small testes in male mice and a delay in vaginal opening and an absence of follicular maturation in female mice), but they showed responsiveness to both exogenous gonadotropins and gonadotropin-releasing hormone and had normal levels of gonadotropin-releasing hormone in the hypothalamus. CONCLUSIONS: Mutations in GPR54, a G protein-coupled receptor gene, cause autosomal recessive idiopathic hypogonadotropic hypogonadism in humans and mice, suggesting that this receptor is essential for normal gonadotropin-releasing hormone physiology and for puberty.


Assuntos
Gonadotropinas/deficiência , Hipogonadismo/genética , Puberdade/genética , Receptores de Neuropeptídeos/genética , Animais , Análise Mutacional de DNA , Feminino , Genes Recessivos , Hormônio Liberador de Gonadotropina/sangue , Gonadotropinas/sangue , Gônadas/patologia , Humanos , Escore Lod , Masculino , Camundongos , Camundongos Knockout , Modelos Animais , Mutação , Linhagem , Fenótipo , Receptores Acoplados a Proteínas G , Receptores de Kisspeptina-1 , Receptores de Neuropeptídeos/deficiência , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Maturidade Sexual/genética
4.
Neuron ; 38(5): 715-30, 2003 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-12797957

RESUMO

Narcolepsy-cataplexy, a neurological disorder associated with the absence of hypothalamic orexin (hypocretin) neuropeptides, consists of two underlying problems: inability to maintain wakefulness and intrusion of rapid eye movement (REM) sleep into wakefulness. Here we document, using behavioral, electrophysiological, and pharmacological criteria, two distinct classes of behavioral arrests exhibited by mice deficient in orexin-mediated signaling. Both OX2R(-/-) and orexin(-/-) mice are similarly affected with behaviorally abnormal attacks of non-REM sleep ("sleep attacks") and show similar degrees of disrupted wakefulness. In contrast, OX2R(-/-) mice are only mildly affected with cataplexy-like attacks of REM sleep, whereas orexin(-/-) mice are severely affected. Absence of OX2Rs eliminates orexin-evoked excitation of histaminergic neurons in the hypothalamus, which gate non-REM sleep onset. While normal regulation of wake/non-REM sleep transitions depends critically upon OX2R activation, the profound dysregulation of REM sleep control unique to the narcolepsy-cataplexy syndrome emerges from loss of signaling through both OX2R-dependent and OX2R-independent pathways.


Assuntos
Vias Eferentes/metabolismo , Hipotálamo/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular , Narcolepsia/genética , Neuropeptídeos/deficiência , Receptores de Neuropeptídeos/deficiência , Sono REM/genética , Sono/genética , Animais , Nível de Alerta/genética , Proteínas de Transporte/genética , Células Cultivadas , Clomipramina/farmacologia , Modelos Animais de Doenças , Vias Eferentes/fisiopatologia , Eletroencefalografia , Eletromiografia , Histamina/metabolismo , Região Hipotalâmica Lateral/metabolismo , Região Hipotalâmica Lateral/fisiopatologia , Hipotálamo/fisiopatologia , Masculino , Camundongos , Camundongos Knockout , Narcolepsia/metabolismo , Narcolepsia/fisiopatologia , Neuropeptídeos/genética , Receptores de Orexina , Orexinas , Receptores Acoplados a Proteínas G , Receptores de Neuropeptídeos/genética , Transmissão Sináptica/genética
5.
J Neurosci ; 21(8): 2912-8, 2001 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-11306643

RESUMO

The somatotropic axis, and particularly growth hormone-releasing hormone (GHRH), is implicated in the regulation of sleep-wake activity. To evaluate sleep in chronic somatotropic deficiency, sleep-wake activity was studied in dwarf (dw/dw) rats that are known to have a defective GHRH signaling mechanism in the pituitary and in normal Lewis rats, the parental strain of the dw/dw rats. In addition, expression of GHRH receptor (GHRH-R) mRNA in the hypothalamus/preoptic region and in the pituitary was also determined by means of reverse transcription-PCR, and GHRH content of the hypothalamus was measured. Hypothalamic/preoptic and pituitary GHRH-R mRNA levels were decreased in the dw/dw rats, indicating deficits in the central GHRHergic transmission. Hypothalamic GHRH content in dw/dw rats was also less than that found in Lewis rats. The dw/dw rats had less spontaneous nonrapid eye movement sleep (NREMS) (light and dark period) and rapid eye movement sleep (REMS) (light period) than did the control Lewis rats. After 4 hr of sleep deprivation, rebound increases in NREMS and REMS were normal in the dw/dw rat. As determined by fast Fourier analysis of the electroencephalogram (EEG), the sleep deprivation-induced enhancements in EEG slow-wave activity in the dw/dw rats were only one-half of the response in the Lewis rats. The results are compared with sleep findings previously obtained in GHRH-deficient transgenic mice. The alterations in NREMS are attributed to the defect in GHRH signaling, whereas the decreases in REMS might result from the growth hormone deficiency in the dw/dw rat.


Assuntos
Nanismo Hipofisário/metabolismo , Hormônio Liberador de Hormônio do Crescimento/deficiência , Receptores de Neuropeptídeos/metabolismo , Receptores de Hormônios Reguladores de Hormônio Hipofisário/metabolismo , Transdução de Sinais , Transtornos Intrínsecos do Sono/metabolismo , Animais , Ritmo Circadiano , Nanismo Hipofisário/complicações , Nanismo Hipofisário/genética , Eletroencefalografia , Hormônio do Crescimento/deficiência , Hormônio Liberador de Hormônio do Crescimento/genética , Hormônio Liberador de Hormônio do Crescimento/metabolismo , Hipotálamo/metabolismo , Masculino , Hipófise/metabolismo , Área Pré-Óptica/metabolismo , RNA Mensageiro/metabolismo , Ratos , Ratos Endogâmicos Lew , Ratos Mutantes , Receptores de Neuropeptídeos/deficiência , Receptores de Neuropeptídeos/genética , Receptores de Hormônios Reguladores de Hormônio Hipofisário/deficiência , Receptores de Hormônios Reguladores de Hormônio Hipofisário/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais/genética , Privação do Sono , Transtornos Intrínsecos do Sono/complicações , Transtornos Intrínsecos do Sono/diagnóstico , Fases do Sono/genética
7.
Cell ; 98(4): 437-51, 1999 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-10481909

RESUMO

Neurons containing the neuropeptide orexin (hypocretin) are located exclusively in the lateral hypothalamus and send axons to numerous regions throughout the central nervous system, including the major nuclei implicated in sleep regulation. Here, we report that, by behavioral and electroencephalographic criteria, orexin knockout mice exhibit a phenotype strikingly similar to human narcolepsy patients, as well as canarc-1 mutant dogs, the only known monogenic model of narcolepsy. Moreover, modafinil, an anti-narcoleptic drug with ill-defined mechanisms of action, activates orexin-containing neurons. We propose that orexin regulates sleep/wakefulness states, and that orexin knockout mice are a model of human narcolepsy, a disorder characterized primarily by rapid eye movement (REM) sleep dysregulation.


Assuntos
Proteínas de Transporte/metabolismo , Modelos Animais de Doenças , Peptídeos e Proteínas de Sinalização Intracelular , Narcolepsia/genética , Neuropeptídeos/deficiência , Neuropeptídeos/metabolismo , Precursores de Proteínas/deficiência , Idade de Início , Animais , Compostos Benzidrílicos/farmacologia , Compostos Benzidrílicos/uso terapêutico , Proteínas de Transporte/genética , Proteínas de Transporte/fisiologia , Doenças do Cão/genética , Cães , Eletroencefalografia , Eletromiografia , Humanos , Hipotálamo/efeitos dos fármacos , Hipotálamo/fisiopatologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Modafinila , Narcolepsia/tratamento farmacológico , Narcolepsia/metabolismo , Narcolepsia/fisiopatologia , Narcolepsia/veterinária , Neurônios/efeitos dos fármacos , Neurônios/patologia , Neuropeptídeos/genética , Neuropeptídeos/fisiologia , Receptores de Orexina , Orexinas , Fenótipo , Postura , Precursores de Proteínas/genética , Receptores Acoplados a Proteínas G , Receptores de Neuropeptídeos/deficiência , Receptores de Neuropeptídeos/genética , Sono/fisiologia , Sono REM/fisiologia , Especificidade da Espécie , Comportamento Estereotipado
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