Central Precocious Puberty Caused by a Heterozygous Deletion in the MKRN3 Promoter Region

Autor(es):Mostrar menos -

Macedo, Delanie B. ^[1] ; Franca, Monica M. ^[1] ; Montenegro, Luciana R. ^[1] ; Cunha-Silva, Marina ^[1] ; Best, Danielle S. ^[1] ; Abreu, Ana Paula ^{[2, 3]} ; Kaiser, Ursula B. ^{[2, 3]} ; Mendonca, Berenice B. ^[1] ; Jorge, Alexander A. L. ^{[1, 4]} ; Brito, Vinicius N. ^[1] ; Latronico, Ana Claudia ^[1]

Afiliação do(s) autor(es)

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

^[2] Harvard Med Sch, Boston, MA - USA

^[3] Brigham & Womens Hosp, Div Endocrinol Diabet & Hypertens, 75 Francis St, Boston, MA 02115 - USA

^[4] Univ Sao Paulo, Hosp Clin, Fac Med, Unidade Endocrinol Genet LIM25, Sao Paulo - Brazil

• Tipo de documento: Artigo Científico
• Fonte: Neuroendocrinology; v. 107, n. 2, p. 127-132, 2018.
• Citações Web of Science: 6

Resumo

Context: Loss-of-function mutations in the coding region of MKRN3, a maternally imprinted gene at chromosome 15q11.2, are a common cause of familial central precocious puberty (CPP). Whether MKRN3 alterations in regulatory regions can cause CPP has not been explored to date. We aimed to investigate potential pathogenic variants in the promoter region of MKRN3 in patients with idiopathic CPP. Patients/Methods: A cohort of 110 patients with idiopathic CPP was studied. Family history of precocious sexual development was present in 25%. Mutations in the coding region of MKRN3 were excluded in all patients. Genomic DNA was extracted from peripheral blood leukocytes, and 1,100 nucleotides (nt) of the 5'-regulatory region of MKRN3 were amplified and sequenced. Luciferase assays were performed in GT1-7 cells transiently transfected with plasmids containing mutated and wild-type MKRN3 promoter. Results: We identified a rare heterozygous 4-nt deletion (c.-150\_-147delTCAG; -38 to -41 nt upstream to the transcription start site) in the proximal promoter region of MKRN3 in a girl with CPP. In silico analysis predicted that this deletion would lead to the loss of a binding site for a downstream responsive element antagonist modulator (DREAM), a potential transcription factor for MKRN3 and GNRH1 expression. Luciferase assays demonstrated a significant reduction of MKRN3 promoter activity in transfected cells with a c.-150\_-147delTCAG construct plasmid in both homozygous and heterozygous states when compared with cells transfected with the corresponding wild-type MKRN3 promoter region. Conclusion: A rare genetic alteration in the regulatory region of MKRN3 causes CPP. (c) 2018 S. Karger AG, Basel (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
• Modalidade de apoio: 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
• Modalidade de apoio: Bolsas no Brasil - Doutorado Direto
• 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