Novel Genetic and Biochemical Findings of DLK1 in Children with Central Precocious Puberty: A Brazilian–Spanish Study

Abstract

Background Central precocious puberty (CPP) has been associated with loss-of-function mutations in two paternally expressed genes (MKRN3 and DLK1). Rare defects in the DLk1 were also associated with poor metabolic phenotype at adulthood. Objective Our aim was to investigate genetic and biochemical aspects of DLK1 in a Spanish cohort of children with CPP without MKRN3 mutations. Patients A large cohort of children with idiopathic CPP (Spanish PUBERE Registry) was studied. Genomic DNA was obtained from 444 individuals (168 index cases) with CPP and their close relatives. Automatic sequencing of MKRN3 and DLK1 genes were performed. Results Five rare heterozygous mutations of MKRN3 were initially excluded in girls with familial CPP. A rare allelic deletion (c.401_404+8del) in the splice site junction of DLK1 was identified in a Spanish girl with sporadic CPP. Pubertal signs started at 5.7 years. Her metabolic profile was normal. Familial segregation analysis showed that the DLK1 deletion was de novo in the affected child. Serum DLK1 levels were undetectable (<0.4 ng/mL), indicating that the deletion lead to complete lack of DLK1 production. Three others rare allelic variants of DLK1 were also identified (p.Asn134=; g.-222 C>A and g.-223 G>A) in two girls with CPP However, both had normal DLK1 serum levels. Conclusion Loss-of-function mutations of DLK1 represent a rare cause of CPP, reinforcing a significant role of this factor in human pubertal timing.

The first central precocious puberty proteomic profiles revealed multiple metabolic networks and novel key disease-associated proteins

“…Clinical reports suggested central precocious puberty was closely connected with alterations in metabolic factors [ 18 – 20 ]. Central precocious puberty patients with DLK1 defection accompanied with metabolic disturbance including hyperlipidemia, obesity, glucose intolerance et al [ 18 , 19 ]. Adverse metabolic abnormality persistently existed during the therapeutic process even after GnRHa treatment [ 20 ].…”

Pathogenic and Low-Frequency Variants in Children With Central Precocious Puberty

“…Seven SNVs in the DLK1 gene in eight different female CPP patients of our cohort were observed (Supplementary Table S2). Rare pathogenic variants in the DLK1 gene have recently been reported as an infrequent cause of CPP (41)(42)(43), therefore such a connection of the rare SNVs observed in the cases of our cohort as possible associated factors could not be excluded. Up-to-date, DLK1 along with MKRN3 are two of the four known monogenic causes of CPP and that are both imprinted.…”

“…DLK1 is also known as preadipocyte factor 1 (Pref-1) and is involved in the Notch signaling pathway as an adipocyte modulator (40). Studies identified loss-of-function mutations in the DLK1 gene (deletions and frameshifts) as a rare cause of CPP (41)(42)(43), strengthening a significant role of this factor in human pubertal timing and the age of menarche (44).…”

Central precocious puberty: Recent advances in understanding the aetiology and in the clinical approach

“…Patients harbouring DLK1 mutations interestingly present also with metabolic abnormalities, such as glucose intolerance, diabetes, hyperlipidemia and obesity, consistent with some aspects of Temple syndrome (see below). A de novo DLK1 mutation causing CPP without other features of Temple syndrome was recently described 45 . Loss of imprinting of DLK1 has recently been evoked as a probable mechanism of CPP 46 …”