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

Autor:	Montenegro L; Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular/LIM42, Hospital das Clínicas, Departamento de Clínica Médica, Disciplina de Endocrinologia e Metabologia, Faculdade de Medicina, Universidade de São Paulo, São Paulo, 05403-000, Brazil., Seraphim C; Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular/LIM42, Hospital das Clínicas, Departamento de Clínica Médica, Disciplina de Endocrinologia e Metabologia, Faculdade de Medicina, Universidade de São Paulo, São Paulo, 05403-000, Brazil., Tinano F; Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular/LIM42, Hospital das Clínicas, Departamento de Clínica Médica, Disciplina de Endocrinologia e Metabologia, Faculdade de Medicina, Universidade de São Paulo, São Paulo, 05403-000, Brazil.; Division of Endocrinology, Diabetes and Hypertension, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 021115, United States., Piovesan M; Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular/LIM42, Hospital das Clínicas, Departamento de Clínica Médica, Disciplina de Endocrinologia e Metabologia, Faculdade de Medicina, Universidade de São Paulo, São Paulo, 05403-000, Brazil., Canton APM; Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular/LIM42, Hospital das Clínicas, Departamento de Clínica Médica, Disciplina de Endocrinologia e Metabologia, Faculdade de Medicina, Universidade de São Paulo, São Paulo, 05403-000, Brazil., McElreavey K; Human Developmental Genetics Unit, Institute Pasteur, Paris, 75724, France., Brabant S; Assistance Publique Hopitaux de Paris, Department of Functional Explorations, Necker Enfants Malades Hospital, Paris-Centre University, Paris Cedex, 75015, France., Boris NP; Division of Endocrinology, Diabetes and Hypertension, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 021115, United States., Magnuson M; Division of Endocrinology, Diabetes and Hypertension, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 021115, United States., Carroll RS; Division of Endocrinology, Diabetes and Hypertension, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 021115, United States., Kaiser UB; Division of Endocrinology, Diabetes and Hypertension, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 021115, United States., Argente J; Department of Pediatrics, Universidad Autónoma de Madrid, Madrid, 28049, Spain.; Department of Pediatrics & Pediatric Endocrinology, Hospital Infantil Universitario Niño Jesús, Instituto de Investigación La Princesa, Madrid, 28009, Spain.; Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Madrid, 28029, Spain.; IMDEA Food Institute, CEIUAM+CSIC, Madrid, 28049, Spain., Barrios V; Department of Pediatrics, Universidad Autónoma de Madrid, Madrid, 28049, Spain.; Department of Pediatrics & Pediatric Endocrinology, Hospital Infantil Universitario Niño Jesús, Instituto de Investigación La Princesa, Madrid, 28009, Spain.; Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Madrid, 28029, Spain.; IMDEA Food Institute, CEIUAM+CSIC, Madrid, 28049, Spain., Brito VN; Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular/LIM42, Hospital das Clínicas, Departamento de Clínica Médica, Disciplina de Endocrinologia e Metabologia, Faculdade de Medicina, Universidade de São Paulo, São Paulo, 05403-000, Brazil., Brauner R; Pediatric Endocrinology Unit, Hôpital Fondation Adolphe de Rothschild and Université Paris Cité, Paris, 75019, France., Latronico AC; Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular/LIM42, Hospital das Clínicas, Departamento de Clínica Médica, Disciplina de Endocrinologia e Metabologia, Faculdade de Medicina, Universidade de São Paulo, São Paulo, 05403-000, Brazil.
Jazyk:	angličtina
Zdroj:	European journal of endocrinology [Eur J Endocrinol] 2023 Sep 01; Vol. 189 (3), pp. 422-428.
DOI:	10.1093/ejendo/lvad129
Abstrakt:	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. Competing Interests: Conflict of interest: None declared. (© The Author(s) 2023. Published by Oxford University Press on behalf of European Society of Endocrinology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
Databáze:	MEDLINE
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