Six Novel Variants in the <i>MKRN3</i> Gene Causing Central Precocious Puberty

Gernay, Caroline; Brachet, Cécile; Boros, Emese; Tenoutasse, Sylvie; Libioulle, Cécile; Heinrichs, Claudine

doi:10.1210/jendso/bvac168

Cited by 3 publications

(1 citation statement)

References 26 publications

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“…53,[74][75][76] Atualmente são conhecidas mais de 60 diferentes mutações inativadoras deste gene relacionadas à PPC. 10,74,76,77 A maioria dessas mutações são do tipo missense, seguidas por mutações frameshift e, em menor número, nonsense. 10 Foram descritas, ainda, deleções englobando todo o gene e mutações na região promotora associadas à PPC.…”

Section: Ppc Causada Por Mutações Inativadoras Do Mkrn3unclassified

Caracterização clínica e genética da puberdade precoce central familial

Tinano

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Agradeço a Deus por ter colocado tantas pessoas especiais em meu caminho, sem as quais essa tese não seria possível! Aos meus pais, Toninho e Marilene, que me ensinaram desde cedo a buscar o conhecimento e ir atrás dos meus sonhos. Meu pai, exemplo de médico, e minha mãe, a professora mais paciente e didática que já conheci; cada um a seu modo me fizeram o que sou hoje. À minha irmã Andréia, pela amizade, companheirismo, apoio e incentivo; por estar sempre presente e trazer alegria e leveza à minha vida. Poder contar com o porto seguro de vocês foi o que sempre me fez ir mais longe. Obrigada por tanto! Ao meu marido Matheus, que topou a aventura de desbravar a cidade de São Paulo comigo, e depois a aventura ainda maior de me acompanhar no doutorado sanduíche em Boston. Pela compreensão em todos os momentos, pelas "aulas" de Excel e Powerpoint, sem as quais minhas tabelas e apresentações não seriam as mesmas, por escutar meus treinos de apresentações até o ponto de aprender os nomes dos genes, e por me apoiar em tudo que precisei! À minha querida orientadora, Dra. Ana Claudia Latronico, pela confiança, carinho e incentivo. Por me acolher desde o dia em que bati à sua porta, tão perdida e insegura, e me guiar e orientar com maestria por todo o percurso. Pelo entusiasmo contagiante e por me mostrar o quão longe podemos chegar. Você foi e sempre será uma fonte de admiração e inspiração, e me sinto privilegiada em ter sido sua aluna. Ao querido Dr. Vinícius Brito, pessoa de gentileza sem igual, que contribuiu com tanto carinho e dedicação para meu aprendizado no ambulatório e na pesquisa. À Dra. Berenice Mendonça, pelo acolhimento e incentivo, pelo entusiasmo inspirador e por ser esse exemplo de liderança e dedicação. À Lu Montenegro, que me ensinou com tanta paciência e dedicação os procedimentos de bancada e, com seu jeitinho mineiro de ser, me fez me sentir em casa no LIM/42. Obrigada pela amizade, carinho, e por estar sempre disposta a ajudar, mesmo à distância! Aos meus colegas de doutorado que trouxeram leveza e alegria aos meus dias:

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Section: Ppc Causada Por Mutações Inativadoras Do Mkrn3unclassified

Caracterização clínica e genética da puberdade precoce central familial

Tinano

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Novel MKRN3 Missense Mutations Associated With Central Precocious Puberty Reveal Distinct Effects on Ubiquitination

Magnotto

Mancini

Bird

et al. 2023

The Journal of Clinical Endocrinology &Amp; Metabolism

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Context Loss-of-function mutations in the maternally imprinted genes, MKRN3 and DLK1, are associated with central precocious puberty (CPP). Mutations in MKRN3 are the most common known genetic etiology of CPP. Objective To screen patients with CPP for MKRN3 and DLK1 mutations and analyze the effects of identified mutations on protein function in vitro. Setting Five academic medical institutions. Participants Eighty-four unrelated children with CPP (79 females, 5 males) and, when available, their first-degree relatives. Design Sanger sequencing of MKRN3 and DLK1 5’ upstream flanking and coding regions was performed on DNA extracted from peripheral blood leukocytes. Western blot analysis was performed to assess protein ubiquitination profiles. Results Eight heterozygous MKRN3 mutations were identified in 9 unrelated girls with CPP. Five are novel missense mutations, two were previously identified in patients with CPP, and one is a frameshift variant not previously associated with CPP. No pathogenic variants were identified in DLK1. Girls with MKRN3 mutations had an earlier age of initial pubertal signs and higher basal serum LH and FSH compared to girls with CPP without MRKN3 mutations. Western blot analysis revealed that compared to wild-type MKRN3, mutations within the RING finger domain reduced ubiquitination whereas the mutations outside this domain increased ubiquitination. Conclusions MKRN3 mutations were present in 10.7% of our CPP cohort, consistent with previous studies. The novel identified mutations in different domains of MKRN3 revealed different patterns of ubiquitination, suggesting distinct molecular mechanisms by which the loss of MRKN3 results in early pubertal onset.

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Molecular analysis of MKRN3 gene in Turkish girls with sporadic and familial idiopathic central precocious puberty

Kirkgöz

Kaygusuz

Alavanda

et al. 2023

Journal of Pediatric Endocrinology and Metabolism

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Objectives Central precocious puberty (CPP) develops as a result of early stimulation of the hypothalamic-pituitary-gonadal (HPG) axis. The loss-of-function mutations in the Makorin-ring-finger3 (MKRN3) gene appear to be the most common molecular cause of familial CPP. We aimed to identify MKRN3 gene mutations in our CPP cohort and to investigate the frequency of MKRN3 mutations. Methods 102 patients with CPP included. 53 of them had family history of CPP in the first and/or second-degree relatives. MKRN3 gene was analyzed by next-generation sequencing. Results Possible pathogenic variants were found in 2/53 patients with family history of CPP (3.8%) and 1/49 patient without family history (2%). A novel heterozygous c.1A>G (p.Met1Val) mutation, a novel heterozygous c.683_684delCA (p.Ser228*) and a previously reported c.482dupC (Ala162Glyfs*) frameshift variations were detected. The two novel variants are predicted to be pathogenic in silico analyses. Conclusions In our cohort, possible pathogenic variants in MKRN3 gene were detected in 2.9% of the total cohort, 3.8% of the familial and 2% of the nonfamilial cases, slightly lower than that reported in the literature. Two novel variants detected contribute to the molecular repertoire of MKRN3 defects in CPP. Classical pattern of paternal inheritance has been demonstrated in all three cases. However, the father of the patient 3 did not have history of CPP suggesting that the father inherited this variant from his mother and had phenotype skipping. Therefore, we emphasize that the absence of history of CPP in the father does not exclude the possibility of a MKRN3 mutation.

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Six Novel Variants in the MKRN3 Gene Causing Central Precocious Puberty

Cited by 3 publications

References 26 publications

Caracterização clínica e genética da puberdade precoce central familial

Caracterização clínica e genética da puberdade precoce central familial

Novel MKRN3 Missense Mutations Associated With Central Precocious Puberty Reveal Distinct Effects on Ubiquitination

Molecular analysis of MKRN3 gene in Turkish girls with sporadic and familial idiopathic central precocious puberty

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