<i>TAC3</i>and<i>TACR3</i>Defects Cause Hypothalamic Congenital Hypogonadotropic Hypogonadism in Humans

Young, Jacques; Bouligand, Jérôme; Francou, Bruno; Raffin-Sanson, Marie Laure; Gaillez, Stephanie; Jeanpierre, Marc; Grynberg, Michaël; Kamenický, Peter; Chanson, Philippe; Brailly-Tabard, Sylvie; Guiochon‐Mantel, Anne

doi:10.1210/jc.2009-2600

Cited by 214 publications

(192 citation statements)

References 20 publications

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“…43 Interestingly, although kisspeptins do not seem to be mandatory for proper GnRH neuron migration, compelling experimental work has documented that populations of kisspeptin neurons undergo a dynamic process of prenatal and postnatal maturation that enables them to establish connections with GnRH neurons early in development 44 (under the control of steroid hormones [45][46][47] ). Similarly, identification of mutations in TAC3 (encoding tachykinin-3, which is cleaved to form neurokinin-B) and TACR3 (encoding tachykinin receptor 3; also known as neuromedin-K receptor [NKR]) [48][49][50] in patients with CHH highlights the important role of members of the tachykinin family in the control of GnRH neurons. Furthermore, …”

Section: Biology Of the Gnrh Neuronal Systemmentioning

confidence: 99%

“…120,121 Genes involved in CHH that are associated with a normal sense of smell include GNRHR (encoding gonadotropinreleasing hormone receptor), 122,123 GNRH1 (encoding gonadotropin-releasing hormone 1), 124,125 KISS1R, 41,42 KISS1, 40,126 TACR3 and TAC3. [48][49][50] Other genes such as FGFR1 or PROKR2 can be mutated in patients with either Kallmann syndrome or CHH (Table 1). Remarkably, mutations in each Kallmann syndrome or CHH gene identified so far account for <10% of cases.…”

Section: Genetics Of Chhmentioning

confidence: 99%

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European Consensus Statement on congenital hypogonadotropic hypogonadism—pathogenesis, diagnosis and treatment

et al. 2015

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| Congenital hypogonadotropic hypogonadism (CHH) is a rare disorder caused by the deficient production, secretion or action of gonadotropin-releasing hormone (GnRH), which is the master hormone regulating the reproductive axis. CHH is clinically and genetically heterogeneous, with >25 different causal genes identified to date. Clinically, the disorder is characterized by an absence of puberty and infertility. The association of CHH with a defective sense of smell (anosmia or hyposmia), which is found in ~50% of patients with CHH is termed Kallmann syndrome and results from incomplete embryonic migration of GnRHsynthesizing neurons. CHH can be challenging to diagnose, particularly when attempting to differentiate it from constitutional delay of puberty. A timely diagnosis and treatment to induce puberty can be beneficial for sexual, bone and metabolic health, and might help minimize some of the psychological effects of CHH. In most cases, fertility can be induced using specialized treatment regimens and several predictors of outcome have been identified. Patients typically require lifelong treatment, yet ~10-20% of patients exhibit a spontaneous recovery of reproductive function. This Consensus Statement summarizes approaches for the diagnosis and treatment of CHH and discusses important unanswered questions in the field.

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Section: Biology Of the Gnrh Neuronal Systemmentioning

confidence: 99%

Section: Genetics Of Chhmentioning

confidence: 99%

European Consensus Statement on congenital hypogonadotropic hypogonadism—pathogenesis, diagnosis and treatment

et al. 2015

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“…Inactivating mutations of two of these, kisspeptin (KP) and neurokinin B (NKB), or their cognate receptors, recently highlighted the crucial role of these neuropeptides in GnRH neurone activation, as these mutations result in a failure to progress through puberty and in adult infertility [6][7][8][9][10][11] . In addition to these major modulators of GnRH secretion, neuropeptide Y, products of the pro-opiomelanocortin protein, gonadotropin-inhibitory-hormone (GnIH) and neurotransmitters such as gamma amino butyric acid and glutamine also regulate GnRH neurone activity 12,13 .…”

Section: B Sex Steroid-dependent Reproductive Diseasesmentioning

confidence: 99%

“…In 2009, inactivating mutations in the human genes encoding NKB and its cognate receptor, TACR3/NK3R, were shown, like GPR54 mutations, to result in a failure to progress through puberty and in hypogonadotropic hypogonadism in adulthood [9][10][11] . In contrast, the original study of an inactivating mutation in the Tacr3 gene (encoding TACR3) in mice, did not observe reproductive impairment 127 .…”

Section: Introductionmentioning

confidence: 99%

Current and future applications of GnRH, kisspeptin and neurokinin B analogues

Millar

Newton

2013

Nat Rev Endocrinol

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Reproductive hormones impact on all stages of life from gamete production, fertilisation, fetal development and parturition, neonatal development and puberty through to adulthood and senescence.The reproductive hormone cascade has therefore been the target for the development of numerous drugs which modulate its activity at many levels. As the central regulator of the cascade, gonadotropinreleasing hormone (GnRH) agonists and antagonists have found extensive applications in treating a wide range of hormone-dependent deseases such as precocious puberty, prostate cancer, benign prostatic hyperplasia, endometriosis and uterine fibroids, as well as being an essential component of in vitro fertilisation (IVF) protocols. Recently-discovered neuroendocrine peptides, kisspeptin (KP) and neurokinin B (NKB), have also been identified as therapeutic targets and novel agonists and antagonists are being developed as modulators of the cascade upstream of GnRH. Here we review the development and applications of analogues of the major neuroendocrine peptide regulators of the reproductive hormone cascade, GnRH, KP and NKB.

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“…Até o momento, cerca de 40 indivíduos com mutações nos genes TAC3 e TACR3 foram descritos, com uma ampla distribuição mundial e uma grande diversidade étnica (11,(70)(71)(72)(73). Mutações no complexo NKB/ NK3R são uma causa comum de HHIn, ocorrendo em mais de 5% dos indivíduos com HHIn (70).…”

Section: Genes Tac3/tacr3unclassified

Aspectos clínicos e moleculares do hipogonadismo hipogonadotrófico isolado congênito

Tusset

Trarbach

Silveira

et al. 2011

Arq Bras Endocrinol Metab

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O hipogonadismo hipogonadotrófico isolado (HHI) congênito caracteriza-se pela falta completa ou parcial de desenvolvimento puberal em decorrência de defeitos na migração, síntese, secreção ou ação do hormônio liberador de gonadotrofinas (GnRH). Baixas concentrações de esteroides sexuais e valores reduzidos ou inapropriadamente normais de gonadotrofinas hipofisárias (LH e FSH) definem, do ponto de vista laboratorial, essa condição clínica. A secreção dos demais hormônios hipofisários encontra-se normal, bem como a ressonância magnética de região hipotalâmica-hipofisária, demonstrando a ausência de uma causa anatômica. Alterações olfatórias, como anosmia ou hiposmia, podem estar associadas ao HHI, caracterizando a síndrome de Kallmann. Uma lista crescente de genes está envolvida na etiologia do HHI, sugerindo a heterogeneidade e a complexidade da base genética dessa condição. Distúrbios na rota de migração dos neurônios secretores de GnRH e dos neurônios olfatórios formam a base clínico-patológica da síndrome de Kallmann. Mutações nos genes KAL1, FGFR1/FGF8, PROK2/PROKR2, NELF, CHD7, HS6ST1 e WDR11 foram associadas a defeitos de migração neuronal, causando a síndrome de Kallmann. É notável que defeitos nos genes FGFR1, FGF8, PROKR2, CHD7 e WDR11 foram também associados ao HHI sem alterações olfatórias (HHI normósmico), porém em menor frequência. Adicionalmente, defeitos nos KISS1R, TAC3/TACR3 e GNRH1/GNRHR foram descritos exclusivamente em pacientes com HHI normósmico. Neste trabalho, revisaremos as características clínicas, hormonais e genéticas do HHI.

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TAC3andTACR3Defects Cause Hypothalamic Congenital Hypogonadotropic Hypogonadism in Humans

Abstract: Our data demonstrate the hypothalamic origin of the gonadotropin deficiency in these genetic forms of normosmic CHH. Neurokinin B and NK3R therefore both play a crucial role in hypothalamic GnRH release in humans.

Cited by 214 publications

References 20 publications

European Consensus Statement on congenital hypogonadotropic hypogonadism—pathogenesis, diagnosis and treatment

European Consensus Statement on congenital hypogonadotropic hypogonadism—pathogenesis, diagnosis and treatment

Current and future applications of GnRH, kisspeptin and neurokinin B analogues

Aspectos clínicos e moleculares do hipogonadismo hipogonadotrófico isolado congênito

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