Molecular analysis of MKRN3 gene in Turkish girls with sporadic and familial idiopathic central precocious puberty

Abstract

Objectives Central precocious puberty (CPP) develops as a result of early stimulation of the hypothalamic-pituitary-gonadal (HPG) axis. The loss-of-function mutations in the Makorin-ring-finger3 (MKRN3) gene appear to be the most common molecular cause of familial CPP. We aimed to identify MKRN3 gene mutations in our CPP cohort and to investigate the frequency of MKRN3 mutations. Methods 102 patients with CPP included. 53 of them had family history of CPP in the first and/or second-degree relatives. MKRN3 gene was analyzed by next-generation sequencing. Results Possible pathogenic variants were found in 2/53 patients with family history of CPP (3.8%) and 1/49 patient without family history (2%). A novel heterozygous c.1A>G (p.Met1Val) mutation, a novel heterozygous c.683_684delCA (p.Ser228*) and a previously reported c.482dupC (Ala162Glyfs*) frameshift variations were detected. The two novel variants are predicted to be pathogenic in silico analyses. Conclusions In our cohort, possible pathogenic variants in MKRN3 gene were detected in 2.9% of the total cohort, 3.8% of the familial and 2% of the nonfamilial cases, slightly lower than that reported in the literature. Two novel variants detected contribute to the molecular repertoire of MKRN3 defects in CPP. Classical pattern of paternal inheritance has been demonstrated in all three cases. However, the father of the patient 3 did not have history of CPP suggesting that the father inherited this variant from his mother and had phenotype skipping. Therefore, we emphasize that the absence of history of CPP in the father does not exclude the possibility of a MKRN3 mutation.

Caracterização clínica e genética da puberdade precoce central familial

“…28,71,72 Todavia, elas parecem ser menos comuns em determinadas populações, como a coreana e outras populações asiáticas; 71,73 e uma menor frequência entre os casos familiais foi reportada em alguns estudos (3,8 a 15,7%). 53,[74][75][76] Atualmente são conhecidas mais de 60 diferentes mutações inativadoras deste gene relacionadas à PPC. 10,74,76,77 A maioria dessas mutações são do tipo missense, seguidas por mutações frameshift e, em menor número, nonsense.…”

“…53,[74][75][76] Atualmente são conhecidas mais de 60 diferentes mutações inativadoras deste gene relacionadas à PPC. 10,74,76,77 A maioria dessas mutações são do tipo missense, seguidas por mutações frameshift e, em menor número, nonsense. 10 Foram descritas, ainda, deleções englobando todo o gene e mutações na região promotora associadas à PPC.…”