Neuroendocrine Phenotype Analysis in Five Patients with Isolated Hypogonadotropic Hypogonadism due to a L102P Inactivating Mutation of GPR54

Tenenbaum‐Rakover, Yardena; Commenges-Ducos, M.; Iovane, André; Aumas, Chantal; Admoni, Osnat; Roux, Nicolas de

doi:10.1210/jc.2006-2147

Cited by 155 publications

(143 citation statements)

References 40 publications

(46 reference statements)

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“…These mutations include six point mutations (p.L148S, p.R297L, p.C223R, p.R331X, p.X399R, and p.L102P) (3,5,14), one 155-bp deletion (4), and one insertion (c.1001_1002insC) (6). Taking into consideration the 312 patients with normosmic IHH reported to have been screened, including the 69 patients from this study, mutations reported in KISS1R gene are responsible for !5% of cases of normosmic IHH.…”

Section: Discussionmentioning

confidence: 99%

A novel homozygous splice acceptor site mutation of KISS1R in two siblings with normosmic isolated hypogonadotropic hypogonadism

Teles

Trarbach

Noel

et al. 2010

European Journal of Endocrinology

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Context: Loss-of-function mutations of the kisspeptin-1 receptor gene, KISS1R, have been identified in patients with normosmic isolated hypogonadotropic hypogonadism (nIHH). Objective: To investigate KISS1R defects in patients with absent or delayed puberty. Patients: We investigated KISS1R gene defects in a cohort of 99 Brazilian patients with nIHH or constitutional delay of puberty (CDP). Methods: The entire coding region of KISS1R was amplified by PCR followed by automatic sequencing. In addition, screening for KISS1R exonic deletions was performed by multiplex ligation-dependent probe amplification. Results: One novel homozygous KISS1R mutation was identified in two siblings with nIHH. This variant was an insertion/deletion (indel) mutation characterized by the deletion of three nucleotides (GCA) at position K2 to K4, and by the insertion of seven nucleotides (ACCGGCT) at the same position, within the 3 0 splice acceptor site of intron 2 of KISS1R. The brothers who carried this KISS1R mutation had no clinical evidence of pubertal development at the ages of 14 and 20 years. Computational analysis of this indel mutation predicted the generation of an abnormal protein. In addition, a new heterozygous KISS1R variant (p.E252Q) was identified in a male patient with sporadic nIHH. However, in vitro studies of this variant did not demonstrate functional impairment. Only known polymorphisms were identified in patients with CDP. Conclusion: Loss-of-function mutations of KISS1R represents a rare cause of nIHH, and was absent in patients with CDP. We have described a novel KISS1R homozygous splice acceptor site mutation in the familial form of nIHH.

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Section: Discussionmentioning

confidence: 99%

A novel homozygous splice acceptor site mutation of KISS1R in two siblings with normosmic isolated hypogonadotropic hypogonadism

Teles

Trarbach

Noel

et al. 2010

European Journal of Endocrinology

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“…Finally, Tenenbaum-Rakover et al (107) identified five patients with CHH belonging to two unrelated consanguineous Arab-Muslim families from Syria and Israel. All the affected subjects were homozygous for another GPR54/KISS1R missense mutation that replaced a leucine with a proline at residue 102 (L102P), and completely abolished GPR54 signaling.…”

Section: Chh In Patients Carrying Gpr54/kiss1r Mutationsmentioning

confidence: 99%

Non-syndromic congenital hypogonadotropic hypogonadism: clinical presentation and genotype–phenotype relationships

Brioude

Bouligand

Trabado

et al. 2010

European Journal of Endocrinology

102

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Congenital hypogonadotropic hypogonadism (CHH) results from abnormal gonadotropin secretion, and it is characterized by impaired pubertal development. CHH is caused by defective GNRH release, or by a gonadotrope cell dysfunction in the pituitary. Identification of genetic abnormalities related to CHH has provided major insights into the pathways critical for the development, maturation, and function of the reproductive axis. Mutations in five genes have been found specifically in Kallmann's syndrome, a disorder in which CHH is related to abnormal GNRH neuron ontogenesis and is associated with anosmia or hyposmia.In combined pituitary hormone deficiency or in complex syndromic CHH in which gonadotropin deficiency is either incidental or only one aspect of a more complex endocrine disorder or a nonendocrine disorder, other mutations affecting GNRH and/or gonadotropin secretion have been reported.Often, the CHH phenotype is tightly linked to an isolated deficiency of gonadotropin secretion. These patients, who have no associated signs or hormone deficiencies independent of the deficiency in gonadotropin and sex steroids, have isolated CHH. In some familial cases, they are due to genetic alterations affecting GNRH secretion (mutations in GNRH1, GPR54/KISS1R and TAC3 and TACR3) or the GNRH sensitivity of the gonadotropic cells (GNRHR). A minority of patients with Kallmann's syndrome or a syndromic form of CHH may also appear to have isolated CHH, but close clinical, familial, and genetic studies can reorient the diagnosis, which is important for genetic counseling in the context of assisted reproductive medicine.This review focuses on published cases of isolated CHH, its clinical and endocrine features, genetic causes, and genotype-phenotype relationships.

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“…Análises de segregação familiar realizadas nessas famílias mostraram que os indiví-duos portadores de alterações no gene KISS1R em heterozigose apresentavam um desenvolvimento puberal normal, confirmando um modelo de herança autossô-mica recessiva para essa doença. Mutações no KISS1R são consideradas uma causa rara de HHI, com uma frequên cia inferior a 5% em casos esporádicos (1,6%), porém com uma frequência mais elevada entre os casos familiares (20,8%) (6,10,(63)(64)(65).…”

Section: Defeitos Na Síntese E Secreção De Gnrh Gene Kiss1runclassified

“…O fenótipo reprodutivo desses indivíduos varia de hipogonadismo parcial a completo. De modo geral, o perfil neuroendócrino desses pacientes revela baixa amplitude dos pulsos de LH, sugerindo uma secreção reduzida de GnRH (10,65). É notável que tanto homens quanto mulheres portadores de mutações no KISS1R apresentam resultados satisfatórios no tratamento, seja ele realizado com a administração exógena de gonadotrofinas ou com infusão de GnRH pulsátil a longo prazo (10,63,65,66).…”

Section: Defeitos Na Síntese E Secreção De Gnrh Gene Kiss1runclassified

“…De modo geral, o perfil neuroendócrino desses pacientes revela baixa amplitude dos pulsos de LH, sugerindo uma secreção reduzida de GnRH (10,65). É notável que tanto homens quanto mulheres portadores de mutações no KISS1R apresentam resultados satisfatórios no tratamento, seja ele realizado com a administração exógena de gonadotrofinas ou com infusão de GnRH pulsátil a longo prazo (10,63,65,66). De fato, camundongos com ablação dos genes KISS1 e KISS1R não desenvolvem puberdade normal e exibem fenótipo de HHI, porém vale ressaltar que nesses animais os neurônios secretores de GnRH estão anatomicamente intactos e apresentam conteúdo normal de GnRH, sugerindo um papel na regulação da secreção de GnRH (66-69).…”

Section: Defeitos Na Síntese E Secreção De Gnrh Gene Kiss1runclassified

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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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Neuroendocrine Phenotype Analysis in Five Patients with Isolated Hypogonadotropic Hypogonadism due to a L102P Inactivating Mutation of GPR54

Abstract: GPR54 inactivation does not impede neuroendocrine onset of puberty; rather, it delays and slows down pubertal maturation of the gonadotropic axis. The L102P loss of function mutation in GPR54 results in a more quantitative than qualitative defect of gonadotropic axis activation.

Cited by 155 publications

References 40 publications

A novel homozygous splice acceptor site mutation of KISS1R in two siblings with normosmic isolated hypogonadotropic hypogonadism

A novel homozygous splice acceptor site mutation of KISS1R in two siblings with normosmic isolated hypogonadotropic hypogonadism

Non-syndromic congenital hypogonadotropic hypogonadism: clinical presentation and genotype–phenotype relationships

Aspectos clínicos e moleculares do hipogonadismo hipogonadotrófico isolado congênito

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