Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2023 Sep 1;189(3):422-428.
doi: 10.1093/ejendo/lvad129.

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

Luciana Montenegro  1 , Carlos Seraphim  1 , Flávia Tinano  1   2 , Maiara Piovesan  1 , Ana P M Canton  1 , Ken McElreavey  3 , Severine Brabant  4 , Natalia P Boris  2 , Melissa Magnuson  2 , Rona S Carroll  2 , Ursula B Kaiser  2 , Jesús Argente  5   6   7   8 , Vicente Barrios  5   6   7   8 , Vinicius N Brito  1 , Raja Brauner  9 , Ana Claudia Latronico  1
Affiliations

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

Luciana Montenegro et al. Eur J Endocrinol. .

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.

Keywords: DLK1 mutations; DLK1 levels; central precocious puberty; pubertal timing.

PubMed Disclaimer

Conflict of interest statement

Conflict of interest: None declared.

Figures

Figure 1.
Figure 1.
Pedigrees of the 2 families and sequencing data of the DLK1 gene showing rare allelic variants. A. Electropherogram of index patient 1 and her relatives. I) Index case harboring the DLK1 pathogenic allelic variant c.372C>A; p.Cys124X—(rs749564412). II) Normal electropherogram of her mother. III) Her father is an asymptomatic carrier of the mutation. B. Electropherogram of index patient 2 and her relatives. I) Index case harboring the DLK1 pathogenic allelic variant c.2T>G p.Met1?, or p.0. II) The father of index case 2, harboring the pathogenic allelic variant and transmitting it to the index case, to the sister, and to her half-sister. III and IV) Paternal half-sisters of the index patient 2. V and VI) Normal electropherogram of the index’s mother and the paternal half-sister’s mother, respectively. C and D. Family pedigrees of patients 1 and 2, respectively. Squares indicate male members, circles female members, solid symbols affected members, dot symbol indicates that the subject is a carrier, and question marks indicate members who were not evaluated. The index case is indicated by an arrow. CPP, central precocious puberty.
Figure 2.
Figure 2.
Schematic representation of the human DLK1 gene and human DLK1 protein. A. Human DLK1 gene (transcript ENST00000341267.9): The boxes indicate the coding sequences of the 5 exons of the gene in humans. Open boxes indicate the 5′- and 3′-untranslated regions of the gene, respectively. Previously described mutations are indicated by arrows. The 2 new mutations found in this work are indicated by arrows in bold. B. Human DLK1 protein structure (P80370): The hexagon indicates the signaling peptide; circles the 6 EGF-like repeats. The rhomboid indicates the extracellular TACE (ADAM17) proteolytic cleavage domain. The trapeze figure indicates the transmembrane domain, and the diamond represents the cytoplasmic domain. The numbers below the figure represent the amino acid positions of the indicated domains. Corresponding protein sequences of the previously mutations described are shown by arrows. The 2 new mutations found in this work are indicated by arrows in bold. EGF, epidermal growth factor (EGF).
Figure 3.
Figure 3.
Serum DLK1 levels in normal puberty vs idiopathic CPP. Box plots represent the serum DLK1 levels in normal puberty subjects (control) and in CPP subjects. CPP, central precocious puberty.
Figure 4.
Figure 4.
DLK1 levels in girls and boys according to Tanner stages. DLK1 levels according to puberty Tanner stages in (A) girls and (B) boys.
Figure 5.
Figure 5.
DLK1 according to BMI SDS and age. A. DLK1 levels vs BMI SDS in girls. B. DLK1 levels vs BMI SDS in boys. C. DLK1 levels in obese/overweight vs normal weight subjects. BMI, body mass index.
Figure 6.
Figure 6.
Circulating serum Dlk1 levels in peripubertal female mice. Serum Dlk1 levels of 5 female mice followed longitudinally across pubertal maturation. The mice were all weaned at age 21 days. Vaginal opening (VO) occurred at age 25.6 ± 1.9 days (mean ± SEM), and first estrous (FE) at age 37.6 ± 2.6 days (mean ± SEM). The dots connected by lines represent the same animal at the different pubertal stages, and the bars indicate the mean level at each stage (considering all mice together). Significant differences between serum Dlk1 levels at the various pubertal stages assessed are indicated with different letters (a to d) (P < .05), as determined by 1-way ANOVA.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

References

    1. Falix FA, Aronson DC, Lamers WH, Gaemers IC. Possible roles of DLK1 in the Notch pathway during development and disease. Biochim Biophys Acta. 2012;1822(6):988–995. 10.1016/j.bbadis.2012.02.003 - DOI - PubMed
    1. Baladrón V, Ruiz-Hidalgo MJ, Nueda ML, et al. . Dlk acts as a negative regulator of Notch1 activation through interactions with specific EGF-like repeats. Exp Cell Res. 2005;303(2):343–359. 10.1016/j.yexcr.2004.10.001 - DOI - PubMed
    1. D'Souza B, Meloty-Kapella L, Weinmaster G. Canonical and non-canonical Notch ligands. Curr Top Dev Biol. 2010;92:73–129. 10.1016/S0070-2153(10)92003-6 - DOI - PMC - PubMed
    1. Henrique D, Schweisguth F. Mechanisms of Notch signaling: a simple logic deployed in time and space. Development. 2019;146(3):dev172148. 10.1242/dev.172148 - DOI - PubMed
    1. Dauber A, Cunha-Silva M, Macedo DB, et al. . Paternally inherited DLK1 deletion associated with familial central precocious puberty. J Clin Endocrinol Metab. 2017;102(5):1557–1567. 10.1210/jc.2016-3677 - DOI - PMC - PubMed