DLK1 Is a Novel Link Between Reproduction and Metabolism

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Games, Larissa G. ^[1] ; Cunha-Silva, Marina ^[1] ; Crespo, Raiane P. ^[1] ; Ramos, Carolina O. ^[1] ; Montenegro, Luciana R. ^{[1, 2]} ; Canton, Ana ^[1] ; Lees, Melissa ^[3] ; Spoudeas, Helen ^[3] ; Dauber, Andrew ^[4] ; Macedo, Delanie B. ^[1] ; Bessa, Danielle S. ^[1] ; Maciel, Gustavo A. ^[5] ; Baracat, Edmund C. ^[5] ; Jorge, Alexander A. L. ^[6] ; Mendonca, Berenice B. ^{[1, 2]} ; Brito, Vinicius N. ^[1] ; Latronico, Ana Claudia ^[1]

Afiliação do(s) autor(es)

^[1] Univ Sao Paulo, Unidade Endocrinol Desenvolvimento, Lab Hormonios & Genet Mol LIM42, Disciplina Endocrinol & Metab, Hosp Clin, Fac Med, BR-05403000 Sao Paulo - Brazil

^[2] Univ Sao Paulo, Fac Med, Lab Sequenciamento Larga Escala, BR-01246903 Sao Paulo - Brazil

^[3] Great Ormond St Hosp Sick Children, Clin Genet Dept, London WC1N 3JH - England

^[4] Childrens Natl Hlth Syst, Div Endocrinol, Washington, DC 20010 - USA

^[5] Univ Sao Paulo, Fac Med, Disciplina Ginecol, BR-05403000 Sao Paulo - Brazil

^[6] Univ Sao Paulo, Fac Med, Unidade Endocrinol Genet LIM 25, Hosp Clin, Disciplina Endocrinol, BR-01246903 Sao Paulo - Brazil

• Tipo de documento: Artigo Científico
• Fonte: JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM; v. 104, n. 6, p. 2112-2120, JUN 2019.
• Citações Web of Science: 6

Resumo

Background: Delta-like homolog 1 (DLK1), also called preadipocyte factor 1, prevents adipocyte differentiation and has been considered a molecular gatekeeper of adipogenesis. A DLK1 complex genomic defect was identified in five women from a single family with central precocious puberty (CPP) and increased body fat percentage. Methods: We studied 60 female patients with a diagnosis of CPP or history of precocious menarche. Thirty-one of them reported a family history of precocious puberty. DLK1 DNA sequencing was performed in all patients. Serum DLK1 concentrations were measured using an ELISA assay in selected cases. Metabolic and reproductive profiles of adult women with CPP caused by DLK1 defects were compared with those of 20 women with idiopathic CPP. Results: We identified three frameshift mutations of DLK1 (p.Gly199Alafs{*}11, p.Va1271Cysfs{*}14, and p.Pro160Leufs{*}50) in five women from three families with CPP. Segregation analysis was consistent with the maternal imprinting of DLK1. Serum DLK1 concentrations were undetectable in three affected women. Metabolic abnormalities, such as overweight/obesity, early-onset glucose intolerance/type 2 diabetes mellitus, and hyperlipidemia, were more prevalent in women with the DLK1 mutation than in the idiopathic CPP group. Notably, the human metabolic alterations were similar to the previously described dlk1-null mice phenotype. Two sisters who carried the p.Gly199Alafs{*}11 mutation also exhibited polycystic ovary syndrome and infertility. Conclusions: Loss-of-function mutations of DLK1 are a definitive cause of familial CPP. The high prevalence of metabolic alterations in adult women who experienced CPP due to DLK1 defects suggests that this antiadipogenic factor represents a link between reproduction and metabolism. (AU)

• Processo FAPESP: 16/14803-6 - III Simpósio de Integração Acadêmica e Científica entre as Faculdades de Medicina da USP e de Michigan
• Beneficiário: Ana Claudia Latronico Xavier
• Modalidade de apoio: Auxílio Organização - Reunião Científica
• Processo FAPESP: 14/50137-5 - Caracterização molecular de doenças monogênicas do desenvolvimento por sequenciamento em larga escala
• Beneficiário: Berenice Bilharinho de Mendonça
• Modalidade de apoio: Auxílio à Pesquisa - Programa Equipamentos Multiusuários
• Processo FAPESP: 15/17350-0 - Identificação de Genes Associados à Etiologia da Síndrome dos Ovários Policísticos por Sequenciamento em Larga Escala
• Beneficiário: Larissa Garcia Gomes
• Modalidade de apoio: Auxílio à Pesquisa - Regular