Familial central precocious puberty due to DLK1 deficiency: novel genetic findings and relevance of serum DLK1 levels

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Montenegro, Luciana ; Seraphim, Carlos ; Tinano, Flavia ; Piovesan, Maiara ; Canton, Ana P. M. ; Mcelreavey, Ken ; Brabant, Severine ; Boris, Natalia P. ; Magnuson, Melissa ; Carroll, Rona S. ; Kaiser, Ursula B. ; Argente, Jesus ; Barrios, Vicente ; Brito, Vinicius N. ; Brauner, Raja ; Latronico, Ana Claudia

• Tipo de documento: Artigo Científico
• Fonte: EUROPEAN JOURNAL OF ENDOCRINOLOGY; v. 189, n. 3, p. 7-pg., 2023-09-01.

Resumo

Background: Several rare loss-of-function mutations of delta-like noncanonical notch ligand 1 (DLK1) have been described in non-syndromic children with familial central precocious puberty (CPP). Objective: We investigated genetic abnormalities of DLK1 gene in a French cohort of children with idiopathic CPP. Additionally, we explored the pattern of DLK1 serum levels in patients with CPP and in healthy children at puberty, as well as in wild-type female mice. Patients and Methods: Genomic DNA was obtained from 121 French index cases with CPP. Automated sequencing of the coding region of the DLK1 gene was performed in all cases. Serum DLK1 levels were measured by enzyme linked immunosorbent assay (ELISA) in 209 individuals, including 191 with normal pubertal development and in female mice during postnatal pubertal maturation. Results: We identified 2 rare pathogenic DLK1 allelic variants: A stop gain variant (c.372C>A; p.Cys124X) and a start loss variant (c.2T>G; p.Met1?, or p.0) in 2 French girls with CPP. Mean serum DLK1 levels were similar between healthy children and idiopathic CPP children. In healthy individuals, DLK1 levels correlated with pubertal stage: In girls, DLK1 decreased between Tanner stages III and V, whereas in boys, DLK1 decreased between Tanner stages II and V (P =.008 and.016, respectively). Serum levels of Dlk1 also decreased in wild-type female mice. Conclusions: Novel loss-of-function mutations in DLK1 gene were identified in 2 French girls with CPP. Additionally, we demonstrated a pattern of dynamic changes in circulating DLK1 serum levels in humans and mice during pubertal stages, reinforcing the role of this factor in pubertal timing. (AU)

• Processo FAPESP: 22/04870-9 - Expressão hipotalâmica de DLK1 e MeCP2 em camundongos ao longo do desenvolvimento puberal
• Beneficiário: Flávia Rezende Tinano
• Modalidade de apoio: Bolsas no Exterior - Estágio de Pesquisa - Doutorado Direto
• Processo FAPESP: 21/12205-2 - Investigação das bases genéticas da Puberdade Precoce Central Familial de herança materna
• Beneficiário: Flávia Rezende Tinano
• Modalidade de apoio: Bolsas no Brasil - Doutorado Direto
• Processo FAPESP: 19/27631-7 - Estudos genéticos e epigenéticos dos distúrbios endócrinos do eixo reprodutivo
• Beneficiário: Ana Claudia Latronico Xavier
• Modalidade de apoio: Auxílio à Pesquisa - Temático
• Processo FAPESP: 22/00719-4 - Ampla investigação genética e epigenética de pacientes com puberdade precoce central sindrômica
• Beneficiário: Ana Pinheiro Machado Canton
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado