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Paternally Inherited DLK1 Deletion Associated With Familial Central Precocious Puberty

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Dauber, Andrew ; Cunha-Silva, Marina ; Macedo, Delanie B. ; Brito, Vinicius N. ; Abreu, Ana Paula ; Roberts, Stephanie A. ; Montenegro, Luciana R. ; Andrew, Melissa ; Kirby, Andrew ; Weirauch, Matthew T. ; Labilloy, Guillaume ; Bessa, Danielle S. ; Carroll, Rona S. ; Jacobs, Dakota C. ; Chappell, Patrick E. ; Mendonca, Berenice B. ; Haig, David ; Kaiser, Ursula B. ; Latronico, Ana Claudia
Número total de Autores: 19
Tipo de documento: Artigo Científico
Fonte: JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM; v. 102, n. 5, p. 1557-1567, MAY 1 2017.
Citações Web of Science: 33

Context: Central precocious puberty (CPP) results from premature activation of the hypothalamic-pituitary- gonadal axis. Few genetic causes of CPP have been identified, with the most common being mutations in the paternally expressed imprinted gene MKRN3. Objective: To identify the genetic etiology of CPP in a large multigenerational family. Design: Linkage analysis followed by whole-genome sequencing was performed in a family with five female members with nonsyndromic CPP. Detailed phenotyping was performed at the time of initial diagnosis and long-term follow-up, and circulating levels of Delta-like 1 homolog (DLK1) were measured in affected individuals. Expression of DLK1 was measured in mouse hypothalamus and in kisspeptin-secreting neuronal cell lines in vitro. Setting: Endocrine clinic of an academic medical center. Patients: Patients with familial CPP were studied. Results: A complex defect of DLK1 (similar to 14-kb deletion and 269-bp duplication) was identified in this family. This deletion included the 50 untranslated region and the first exon of DLK1, including the translational start site. Only family members who inherited the defect from their father have precocious puberty, consistent with the known imprinting of DLK1. The patients did not demonstrate additional features of the imprinted disorder Temple syndrome except for increased fat mass. Serum DLK1 levels were undetectable in all affected individuals. Dlk1 was expressed in mouse hypothalamus and in kisspeptin neuron-derived cell lines. Conclusion: We identified a genomic defect in DLK1 associated with isolated familial CPP. MKRN3 and DLK1 are both paternally expressed imprinted genes. These findings suggest a role of genomic imprinting in regulating the timing of human puberty. (AU)

Processo FAPESP: 13/03236-5 - Novas abordagens e metodologias na investigação genético-molecular dos distúrbios de crescimento e desenvolvimento puberal
Beneficiário:Alexander Augusto de Lima Jorge
Linha de fomento: Auxílio à Pesquisa - Temático
Processo FAPESP: 13/06391-1 - Novas perspectivas no estudo genético da puberdade precoce central idiopática
Beneficiário:Francisca Delanie Bulcão de Macêdo
Linha de fomento: Bolsas no Brasil - Doutorado Direto