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

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Seraphim, Carlos Eduardo ^[1] ; Canton, Ana Pinheiro Machado ^[1] ; Montenegro, Luciana ^[1] ; Piovesan, Maiara Ribeiro ^[1] ; Macedo, Delanie B. ^[2] ; Cunha, Marina ^[1] ; Guimaraes, Aline ^[1] ; Oliveira Ramos, Carolina ^[1] ; Figueiredo Benedetti, Anna Flavia ^[1] ; de Castro Leal, Andrea ^[3] ; Gagliardi, Priscila C. ^[4] ; Antonini, Sonir R. ^[5] ; Gryngarten, Mirta ^[6] ; Arcari, Andrea J. ^[6] ; Abreu, Ana Paula ^[2] ; Kaiser, Ursula B. ^[2] ; Soriano-Guillen, Leandro ^[7] ; Escribano-Munoz, Arancha ^[8] ; Corripio, Raquel ^[9] ; Labarta, I, Jose ; Travieso-Suarez, Lourdes ^{[10, 11]} ; Valentina Ortiz-Cabrera, Nelmar ^{[10, 11]} ; Argente, Jesus ^{[10, 11]} ; Mendonca, Berenice B. ^[1] ; Brito, Vinicius N. ^[1] ; Claudia Latronico, Ana ^[1]

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^[1] Univ Sao Paulo, Lab Hormonios & Genet Mol LIM 42, Unidade Endocrinol Desenvolvimento, Hosp Clin, Fac Med, Sao Paulo - Brazil

^[2] Harvard Med Sch, Brigham & Womens Hosp, Dept Med, Div Endocrinol Diabet & Hypertens, Boston, MA 02115 - USA

^[3] Univ Estado UEPA, Dept Saude Integrada, Santarem, Para - Brazil

^[4] Nemours Childrens Clin, Div Endocrinol Diabet & Metab, Jacksonville, FL 32207 - USA

^[5] Univ Sao Paulo, Ribeirao Preto Med Sch, Dept Pediat, Ribeirao Preto - Brazil

^[6] Hosp Ninos Dr Ricardo Gutierrez, Ctr Invest Endocrinol Dr Cesar Bergada, CONICET, FEI, Div Endocrinol, Buenos Aires, DF - Argentina

^[7] Univ Autonoma Madrid, IIS Fdn Jimenez Diaz, Dept Pediat, Spanish PUBERE Registry, Madrid - Spain

^[8] Univ Hosp Virgen Arrixaca, Dept Pediat, Endocrinol Unit, Spanish PUBERE Registry, Murcia - Spain

^[9] Univ Autonoma Barcelona, Corp Parc Tauli Hosp Univ, Inst Invest & Innovacio Parc Tauli I3PT, Pediat Endocrinol Dept, Spanish PUBERE Registry, Sabadell - Spain

^[10] Hosp Infantil Univ Nino Jesus, Dept Endocrinol, Madrid - Spain

^[11] Univ Autonoma Madrid, Dept Pediat, Inst Salud Carlos III, IMDEA Inst, Spanish PUBERE Registry, CIBER Obes & N, Madrid - Spain

• Tipo de documento: Artigo Científico
• Fonte: JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM; v. 106, n. 4, p. 1041-1050, APR 2021.
• Citações Web of Science: 1

Resumo

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. (AU)

• Processo FAPESP: 13/03236-5 - Novas abordagens e metodologias na investigação genético-molecular dos distúrbios de crescimento e desenvolvimento puberal
• Beneficiário: Alexander Augusto de Lima Jorge
• Modalidade de apoio: Auxílio à Pesquisa - Temático
• Processo FAPESP: 18/03198-0 - Ampla investigação genética de pacientes com Puberdade Precoce Central associada à fenótipos complexos
• Beneficiário: Ana Pinheiro Machado Canton
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado