Mutations of the KISS1 Gene in Disorders of Puberty

Silveira, Letícia Ferreira Gontijo; Noel, Sekoni D.; Silveira-Neto, A. P.; Abreu, Ana Paula; Brito, Vinícius Nahime; Santos, Mariza Gerdulo; Bianco, Suzy D.C.; Kuohung, Wendy; Xu, Shuyun; Gryngarten, Mirta; Escobar, María Eugenia; Arnhold, Ivo Jorge Prado; Mendonca, Berenice B.; Kaiser, Ursula B.; Latrônico, Ana Claudia

doi:10.1210/jc.2009-2421

Cited by 310 publications

(191 citation statements)

References 20 publications

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“…Mutations or SNPs associated with CPP were initially described in KISS1 and KISS1R (7,8,9), but mutations of these genes are very rare in sporadic cases of iCPP (10). A recent whole-exome sequencing study identified mutations in the makorin RING finger 3 (MKRN3) gene in 15 individuals with iCPP (11).…”

Section: Introductionmentioning

confidence: 99%

Mutations in the maternally imprinted gene MKRN3 are common in familial central precocious puberty

Simon

Mekhail

et al. 2016

European Journal of Endocrinology

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Context and objective: Idiopathic central precocious puberty (iCPP) is defined as early activation of the hypothalamicpituitary-gonadal axis in the absence of identifiable central lesions. Mutations of the makorin RING finger 3 (MKRN3) gene are associated with iCPP. We aimed to assess the frequency of MKRN3 mutations in iCPP and to compare the phenotypes of patients with and without MKRN3 mutations. Design: An observational study was carried out on patients recruited at pediatric hospitals in France and Italy. Forty-six index CPP cases were screened for mutations in the MKRN3 coding sequence: 28 index cases of familial cases and 18 cases did not report any familial history of CPP. The endocrine phenotype was compared between MKRN3 mutated and non-mutated patients. Results: MKRN3 mutations were identified in one sporadic and 13 familial cases. We identified five new heterozygous missense mutations predicted to be deleterious for protein function and two frameshift mutations, one new and the other recurrent, predicted to result in truncated proteins. Age at puberty onset varied very little among patients with MKRN3 mutations and puberty occurred earlier in these patients than in those without MKRN3 mutations (6.0 years (5.4-6.0) vs 7.0 years (6.0-7.0), PZ0.01). Conclusions: MKRN3 mutations are common in familial iCPP. MKRN3 is one of the gatekeepers of the postnatal activation of the gonadotropic axis.

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Section: Introductionmentioning

confidence: 99%

Mutations in the maternally imprinted gene MKRN3 are common in familial central precocious puberty

Simon

Mekhail

et al. 2016

European Journal of Endocrinology

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“…Autosomal-dominant mutations leading to enhanced biological activity are found in a variety of disorders, including Noonan syndrome (in the MAPK pathway) (15)(16)(17), testotoxicosis (in the LH receptor) (18) and in central precocious puberty (in the ligand for GPR54, kisspeptin) (19). A number of possible mechanisms for this putative increased leptin bioactivity can be proposed: the variant may lead to decreased degradation in serum or an altered balance between free and bound circulating leptin with increased free leptin.…”

Section: Discussionmentioning

confidence: 99%

Reduced appetite and body mass index with delayed puberty in a mother and son: association with a rare novel sequence variant in the leptin gene

Murray

Read²,

Banerjee³

et al. 2011

European Journal of Endocrinology

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Introduction: Leptin deficiency caused by mutations within the leptin gene (LEP) results in severe early onset obesity, hypogonadism, pubertal delay and immune system abnormalities. Constitutional delay in growth and puberty (CDGP) is a common condition seen in paediatric clinics, in which children present with delayed growth and puberty but usually also have a slim body habitus. We hypothesized that LEP variants may play a role in the phenotype seen in CDGP. Aim: To screen a group of children with CDGP for pathogenic sequence variants in LEP. Patients and methods: Denaturing HPLC was used to screen for LEP sequence variants in DNA samples from 78 children with CDGP (predominantly white males) and 112 control subjects. DNA fragments with a WAVE pattern deviant from wild type were directly sequenced. A STAT3 luciferase reporter assay in human embryonic kidney (HEK293) cells transiently transfected with the leptin receptor was used to test activity of mutant leptin. Results: One child with CDGP was identified to be heterozygous for a novel missense variant (c.68COG), which results in a proline to arginine substitution (p.P23R). This sequence variant was not identified in any of the other control subjects, but was identified in his mother who shared a similar phenotype of slim body habitus, reduced appetite and pubertal delay (menarche aged 15 years). The leptin variant showed similar stability in serum compared with wild type and did not demonstrate increased activity in an in vitro reporter gene assay. Conclusions: This is the first report of a sequence variant within the LEP gene associated with reduced body mass index rather than obesity. We hypothesize that this variant has increased bioactivity in vivo.

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“…Вместе с тем до 75 % мальчиков с ППР имеют визуализируе-мые поражения ЦНС, главным образом гипота-ламические гамартомы [72][73][74][75]. Наследственный вариант ППР отмечается в 20-25 % случаев, что свидетельствует о роли генетических факторов в его этиологии [77,78]. В 2008 году была от-мечена роль кисспептинового сигнального пути в патогенезе ППР.…”

Section: особенности регуляции активности кисспептина при преждевремеunclassified

“…Несомненно, сам KISS1 является еще одним очевидным кандидатным геном для объяснения механизмов преждевременного полового созревания. Редкий вариант мутации гена кисспептина, р.P74S, был выявлен у ребен-ка со спорадическим ППР [78]. Мутация р.P74S в гетерозиготном состоянии была выявлена у мальчика, у которого появилось ППР в го-довалом возрасте с очень высокими уровнями базального ЛГ и тестостерона [78].…”

Section: особенности регуляции активности кисспептина при преждевремеunclassified

“…Редкий вариант мутации гена кисспептина, р.P74S, был выявлен у ребен-ка со спорадическим ППР [78]. Мутация р.P74S в гетерозиготном состоянии была выявлена у мальчика, у которого появилось ППР в го-довалом возрасте с очень высокими уровнями базального ЛГ и тестостерона [78]. Несмотря на то что большинство мальчиков с ППР, осо-бенно младше 4 лет, имеют лежащую в основе этого состояния структурную патологию ЦНС [74][75][76], у этого ребенка не было выявлено по-ражений ЦНС.…”

Section: особенности регуляции активности кисспептина при преждевремеunclassified

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Role of Kisspeptine in Regulation of Reproductive Function

et al. 2016

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Research objective: to identify a role of kisspeptine in the regulation of reproduction function.Materials: literature data by foreign authors for the period from 1985 till 2016.Methods: systematic analysis and compilation of information in the literature.Results. The article provides a review of literature data on research of kisspeptine gene and its receptor; it includes description of their role in regulation of reproduction function and mutation in the genes responsible for realization of kisspeptine and neurokinin signaling pathways. Features of kisspeptine secretion in patients with hypogonadotropic hypogonadism, premature sexual development, hyperprolactinemic deficiency of ovaries, polycystic ovarian syndrome, genital endometriosis and opportunity of kisspeptine use in clinical practice as an ovulation trigger are described.Conclusion. It is necessary to carry out further studies for clarification of kisspeptine role in patients with various diseases and the opportunity of its use as a therapeutic target.

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Mutations of the KISS1 Gene in Disorders of Puberty

Abstract: Two KISS1 mutations were identified in unrelated patients with idiopathic CPP. The p.P74S variant was associated with higher kisspeptin resistance to degradation in comparison with the wild type, suggesting a role for this mutation in the precocious puberty phenotype.

Cited by 310 publications

References 20 publications

Mutations in the maternally imprinted gene MKRN3 are common in familial central precocious puberty

Mutations in the maternally imprinted gene MKRN3 are common in familial central precocious puberty

Reduced appetite and body mass index with delayed puberty in a mother and son: association with a rare novel sequence variant in the leptin gene

Role of Kisspeptine in Regulation of Reproductive Function

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