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

• Document type: Journal article
• Source: EUROPEAN JOURNAL OF ENDOCRINOLOGY; v. 189, n. 3, p. 7-pg., 2023-09-01.

Abstract

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)

• FAPESP's process: 22/04870-9 - Hypothalamic expression of DLK1 and MeCP2 in mice across pubertal development
• Grantee: Flávia Rezende Tinano
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate (Direct)
• FAPESP's process: 21/12205-2 - Investigation of genetic basis of Familial Central Precocious Puberty of maternal inheritance
• Grantee: Flávia Rezende Tinano
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• FAPESP's process: 19/27631-7 - Genetic and epigenetic studies of endocrine disorders related with reproductive axis
• Grantee: Ana Claudia Latronico Xavier
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 22/00719-4 - Comprehensive genetic and epigenetic investigation of patients with syndromic central precocious puberty
• Grantee: Ana Pinheiro Machado Canton
• Support Opportunities: Scholarships in Brazil - Post-Doctoral