Central Precocious Puberty That Appears to Be Sporadic Caused by Paternally Inherited Mutations in the Imprinted Gene Makorin Ring Finger 3

Author(s):Show less -

Macedo, Delanie B. ^{[1, 2]} ; Abreu, Ana Paula ^{[1, 2, 3, 4]} ; Reis, Ana Claudia S. ^[5] ; Montenegro, Luciana R. ^{[1, 2]} ; Dauber, Andrew ^{[6, 7]} ; Beneduzzi, Daiane ^{[1, 2]} ; Cukier, Priscilla ^{[1, 2]} ; Silveira, Leticia F. G. ^{[1, 2]} ; Teles, Milena G. ^{[1, 2]} ; Carroll, Rona S. ^{[3, 4]} ; Guerra Junior, Gil ^[8] ; Guaragna Filho, Guilherme ^[8] ; Gucev, Zoran ^[9] ; Arnhold, Ivo J. P. ^{[1, 2]} ; de Castro, Margaret ^[5] ; Moreira, Ayrton C. ^[5] ; Martinelli, Jr., Carlos Eduardo ^[5] ; Hirschhorn, Joel N. ^{[6, 7]} ; Mendonca, Berenice B. ^{[1, 2]} ; Brito, Vinicius N. ^{[1, 2]} ; Antonini, Sonir R. ^[5] ; Kaiser, Ursula B. ^{[3, 4]} ; Latronico, Ana Claudia ^{[1, 2]}

Affiliation

^[1] Univ Sao Paulo, Hosp Clin, Fac Med, Unidade Endocrinol Desenvolvimento, BR-05403900 Sao Paulo - Brazil

^[2] Univ Sao Paulo, Hosp Clin, Fac Med, Lab Hormonios & Genet Mol LIM42, Disciplina Endocr, BR-05403900 Sao Paulo - Brazil

^[3] Brigham & Womens Hosp, Div Endocrinol Diabet & Hypertens, Boston, MA 02115 - USA

^[4] Harvard Univ, Sch Med, Boston, MA 02115 - USA

^[5] Univ Sao Paulo, Fac Med Ribeirao Preto, Dept Puericultura & Pediat, BR-14049900 Ribeirao Preto, SP - Brazil

^[6] Boston Childrens Hosp, Div Endocrinol, Boston, MA 02115 - USA

^[7] Program Med & Populat Genet Broad Inst, Cambridge, MA 02142 - USA

^[8] Univ Estadual Campinas, Unidade Endocrinol Pediat, BR-13084970 Campinas, SP - Brazil

^[9] Univ Skopje, Skopje 1000 - Macedonia

• Document type: Journal article
• Source: JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM; v. 99, n. 6, p. E1097-E1103, JUN 2014.
• Web of Science Citations: 56

Abstract

Context: Loss-of-function mutations in makorin ring finger 3 (MKRN3), an imprinted gene located on the long arm of chromosome 15, have been recognized recently as a cause of familial central precocious puberty (CPP) in humans. MKRN3 has a potential inhibitory effect on GnRH secretion. Objectives: The objective of the study was to investigate potential MKRN3 sequence variations as well as copy number and methylation abnormalities of the 15q11 locus in patients with apparently sporadic CPP. Setting and Participants: We studied 215 unrelated children (207 girls and eight boys) from three university medical centers with a diagnosis of CPP. All but two of these patients (213 cases) reported no family history of premature sexual development. First-degree relatives of patients with identified MKRN3 variants were included for genetic analysis. Main Outcome Measures: All 215 CPP patients were screened for MKRN3 mutations by automatic sequencing. Multiplex ligation-dependent probe amplification was performed in a partially overlapping cohort of 52 patients. Results: We identified five novel heterozygous mutations in MKRN3 in eight unrelated girls with CPP. Four were frame shift mutations predicted to encode truncated proteins and one was a missense mutation, which was suggested to be deleterious by in silico analysis. All patients with MKRN3mutations had classical features of CPP with a median age of onset at 6 years. Copy number and methylation abnormalities at the 15q11 locus were not detected in the patients tested for these abnormalities. Segregation analysis was possible in five of the eight girls with MKRN3 mutations; in all cases, the mutation was inherited on the paternal allele. Conclusions: We have identified novel inherited MKRN3 defects in children with apparently sporadic CPP, supporting a fundamental role of this peptide in the suppression of the reproductive axis. (AU)

• FAPESP's process: 13/06391-1 - New perspectives of the genetic study of idiopathic central precocious puberty
• Grantee: Francisca Delanie Bulcão de Macêdo
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• FAPESP's process: 05/04726-0 - Molecular characterization of congenital endocrine diseases that affect growth and development
• Grantee: Ana Claudia Latronico Xavier
• Support Opportunities: Research Projects - Thematic Grants