Genotype-Phenotype Correlations in Central Precocious Puberty Caused by MKRN3 Mutations

Abstract

Context: Loss-of-function mutations of makorin RING finger protein 3 (MKRN3) are the most common monogenic cause of familial central precocious puberty (CPP).

Objective: To describe the clinical and hormonal features of a large cohort of patients with CPP due to MKRN3 mutations and compare the characteristics of different types of genetic defects.

Methods: Multiethnic cohort of 716 patients with familial or idiopathic CPP screened for MKRN3 mutations using Sanger sequencing. A group of 156 Brazilian girls with idiopathic CPP (ICPP) was used as control group.

Results: Seventy-one patients (45 girls and 26 boys from 36 families) had 18 different loss-of-function MKRN3 mutations. Eight mutations were classified as severe (70% of patients). Among the 71 patients, first pubertal signs occurred at 6.2 ± 1.2 years in girls and 7.1 ± 1.5 years in boys. Girls with MKRN3 mutations had a shorter delay between puberty onset and first evaluation and higher follicle-stimulating hormone levels than ICPP. Patients with severe MKRN3 mutations had a greater bone age advancement than patients with missense mutations (2.3 ± 1.6 vs 1.6 ± 1.4 years, P = .048), and had higher basal luteinizing hormone levels (2.2 ± 1.8 vs 1.1 ± 1.1 UI/L, P = .018) at the time of presentation. Computational protein modeling revealed that 60% of the missense mutations were predicted to cause protein destabilization.

Conclusion: Inherited premature activation of the reproductive axis caused by loss-of-function mutations of MKRN3 is clinically indistinct from ICPP. However, the type of genetic defect may affect bone age maturation and gonadotropin levels.

Keywords: MKRN3; MKRN3 phenotype; genetic of puberty; precocious puberty.

Figure 1.

Geographic distribution of 71 patients with CPP due to MKRN3 mutations. The larger circles represent higher numbers of cases: 40 in Brazil, 9 in USA, 8 in Spain, 5 in Argentina, 4 in Belgium, 2 in Israel, 1 in Norway, 1 in Australia, and 1 in Turkey.

Figure 2.

Schematic representation of MKRN3 protein and location of severe (red and yellow) and missense (blue) variants. The MKRN3 protein is composed of 3 C3H1 zinc fingers, a MKRN type Cys-His region, and a C3HC4 RING finger. The arrows point to the corresponding region of the mutation in the protein. The promoter region deletion is represented in this image without a corresponding region in the protein because it leads to loss of transcription due to the loss of a DREAM binding site (13).