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

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 chara...

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Detalles Bibliográficos
Autores: Seraphim, CE, Canton, APM, Montenegro, L, Piovesan, MR, Macedo, DB, Cunha, M, Guimaraes, A, Ramos, CO, Benedetti, AFF, Leal, AD, Gagliardi, PC, Antonini, SR, Gryngarten, M, Arcari, AJ, Abreu, AP, Kaiser, UB, Soriano-Guillen, L, Escribano-Munoz, A, Corripio, R, Labarta, JI, Travieso-Suarez, L, Ortiz-Cabrera, NV, Argente, J, Mendonca, BB, Brito, VN, Latronico, AC
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2021
País:España
Institución:Institut d'Investigació i Innovació Parc Taulí (I3PT)
Repositorio:r-I3PT. Repositorio Institucional Producción Científica del Institut d'Investigació i Innovació Parc Taulí
OAI Identifier:oai:i3pt.fundanetsuite.com:p2343
Acceso en línea:https://i3pt.portalinvestigacion.com/publicaciones/2343
Access Level:acceso abierto
Palabra clave:precocious puberty
MKRN3
genetic of puberty
MKRN3 phenotype
Descripción
Sumario: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.

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