title: Central precocious puberty that appears to be sporadic caused by paternally inherited mutations in the imprinted gene makorin ring finger 3.
abstract: BACKGROUND
  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.
  
  
  OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  METHODS
  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 MKRN3 mutations 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.
authors.affiliation: Unidade de Endocrinologia do Desenvolvimento e Laboratório de Hormônios e Genética Molecular/LIM42, Disciplina de Endocrinologia (D.B.M., A.P.A., L.R.M., D.B., P.C., L.F.G.S., M.G.T., I.J.P.A., B.B.M., V.N.B., A.C.L.), Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP, Brasil, 05403-900; Departamento de Puericultura e Pediatria (A.C.S.R., M.C., A.C.M., C.E.M., S.R.A.), Faculdade de Medicina de Ribeirão Preto, da Universidade de São Paulo, Ribeirão Preto, SP, Brasil, 14049900; Division of Endocrinology, Diabetes, and Hypertension (A.P.A., R.S.C., U.B.K.), Brigham and Women's Hospital and Harvard Medical School and Division of Endocrinology, (A.D., J.N.H.) Boston Children's Hospital, Boston, Massachusetts 02115, Program in Medical and Population Genetics Broad Institute (A.D., J.N.H.), Cambridge, Massachusetts 02142; Unidade de Endocrinologia Pediátrica (G.G.J., G.G.F.), Universidade de Campinas, SP, Brasil, 13084-970; and Medical Faculty Skopje (Z.G.), 50 Divizija BB, 1000 Skopje, Macedonia.
authors.forename: Delanie B
authors.initials: DB
authors.lastname: Macedo
authors.forename: Ana Paula
authors.initials: AP
authors.lastname: Abreu
authors.forename: Ana Claudia S
authors.initials: AC
authors.lastname: Reis
authors.forename: Luciana R
authors.initials: LR
authors.lastname: Montenegro
authors.forename: Andrew
authors.initials: A
authors.lastname: Dauber
authors.forename: Daiane
authors.initials: D
authors.lastname: Beneduzzi
authors.forename: Priscilla
authors.initials: P
authors.lastname: Cukier
authors.forename: Leticia F G
authors.initials: LF
authors.lastname: Silveira
authors.forename: Milena G
authors.initials: MG
authors.lastname: Teles
authors.forename: Rona S
authors.initials: RS
authors.lastname: Carroll
authors.forename: Gil Guerra
authors.initials: GG
authors.lastname: Junior
authors.forename: Guilherme Guaragna
authors.initials: GG
authors.lastname: Filho
authors.forename: Zoran
authors.initials: Z
authors.lastname: Gucev
authors.forename: Ivo J P
authors.initials: IJ
authors.lastname: Arnhold
authors.forename: Margaret
authors.initials: M
authors.lastname: de Castro
authors.forename: Ayrton C
authors.initials: AC
authors.lastname: Moreira
authors.forename: Carlos Eduardo
authors.initials: CE
authors.lastname: Martinelli
authors.forename: Joel N
authors.initials: JN
authors.lastname: Hirschhorn
authors.forename: Berenice B
authors.initials: BB
authors.lastname: Mendonca
authors.forename: Vinicius N
authors.initials: VN
authors.lastname: Brito
authors.forename: Sonir R
authors.initials: SR
authors.lastname: Antonini
authors.forename: Ursula B
authors.initials: UB
authors.lastname: Kaiser
authors.forename: Ana Claudia
authors.initials: AC
authors.lastname: Latronico
mesh_terms: D002648:Child; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D005220:Fathers; D005260:Female; D018392:Genomic Imprinting; D006801:Humans; D040582:Inheritance Patterns; D008297:Male; D009154:Mutation; D010375:Pedigree; D011629:Puberty, Precocious / Q000235:genetics*; D012261:Ribonucleoproteins / Q000235:genetics*; D044767:Ubiquitin-Protein Ligases
chemical_list: D012261:Ribonucleoproteins; C119425:MKRN3 protein, human; D044767:Ubiquitin-Protein Ligases