학술논문
Genotype-Phenotype Correlations in Central Precocious Puberty Caused by MKRN3 Mutations
Clinical Research Article
Clinical Research Article
Document Type
Academic Journal
Author
Seraphim, Carlos Eduardo; Canton, Ana Pinheiro Machado; Montenegro, Luciana; Piovesan, Maiara Ribeiro; Macedo, Delanie B.; Cunha, Marina; Guimaraes, Aline; Ramos, Carolina Oliveira; Benedetti, Anna Flavia Figueiredo; Leal, Andrea de Castro; Gagliardi, Priscila C.; Antonini, Sonir R.; Gryngarten, Mirta; Abreu, Ana Paula; Kaiser, Ursula B.; Soriano-Guillen, Leandro; Escribano-Munoz, Arancha; Corripio, Raquel; Labarta, Jose I.; Travieso-Suarez, Lourdes; Ortiz-Cabrera, Nelmar Valentina; Argente, Jesus; Mendonca, Berenice B.; Brito, Vinicius N.; Latronico, Ana Claudia
Source
Journal of Clinical Endocrinology & Metabolism. April 2021, Vol. 106 Issue 4, p1041, 10 p.
Subject
Language
English
ISSN
0021-972X
Abstract
Makorin RING finger 3 (MKRN3) is an intronless gene located inside a region containing an imprinted gene cluster at chromosome 15q11-q13. It undergoes maternal imprinting; therefore, only the paternal allele [...]
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 [+ or -] 1.2 years in girls and 7. 1 [+ or -] 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 [+ or -] 1.6 vs 1.6 [+ or -] 1.4 years, P = .048), and had higher basal luteinizing hormone levels (2.2 [+ or -] 1.8 vs 1.1 [+ or -] 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 lossof-function mutations of MKRN3 is clinically indistinct from ICPP. However, the type of genetic defect may affect bone age maturation and gonadotropin levels. Key Words: precocious puberty, MKRN3, genetic of puberty, MKRN3 phenotype
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 [+ or -] 1.2 years in girls and 7. 1 [+ or -] 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 [+ or -] 1.6 vs 1.6 [+ or -] 1.4 years, P = .048), and had higher basal luteinizing hormone levels (2.2 [+ or -] 1.8 vs 1.1 [+ or -] 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 lossof-function mutations of MKRN3 is clinically indistinct from ICPP. However, the type of genetic defect may affect bone age maturation and gonadotropin levels. Key Words: precocious puberty, MKRN3, genetic of puberty, MKRN3 phenotype