title: Absence of functional LIN28B mutations in a large cohort of patients with idiopathic central precocious puberty.
abstract: OBJECTIVE
  To investigate LIN28B gene variants in children with idiopathic central precocious puberty (CPP).
  
  
  METHODS
  We studied 178 Brazilian children with CPP (171 girls, 16.8% familial cases). A large multiethnic group (1,599 subjects; Multiethnic Cohort, MEC) was used as control. DNA analysis and biochemical in vitro studies were performed.
  
  
  RESULTS
  A heterozygous LIN28B variant, p.H199R, was identified in a girl who developed CPP at 5.2 years. This variant was absent in 310 Brazilian control individuals, but it was found in the same allele frequency in women from the MEC cohort, independent of the age of menarche. Functional studies revealed that when ectopically expressed in cells, the mutant protein was capable of binding pre-let-7 microRNA and inhibiting let-7 expression to the same extent as wild-type Lin28B protein. Other rare LIN28B variants (p.P173P, c.198+ 32_33delCT, g.9575731A>C and c.-11C>T) were identified in CPP patients and controls. Therefore, no functional mutation was identified.
  
  
  CONCLUSIONS
  In vitro studies revealed that the rare LIN28B p.H199R variant identified in a girl with CPP does not affect the Lin28B function in the regulation of let-7 expression. Although LIN28B SNPs were associated with normal pubertal timing, rare variations in this gene do not seem to be commonly involved in the molecular pathogenesis of CPP.
authors.affiliation: Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular/LIM42, Universidade de São Paulo, São Paulo, Brazil.
authors.forename: Acácio P
authors.initials: AP
authors.lastname: Silveira-Neto
authors.forename: Leticia Ferro
authors.initials: LF
authors.lastname: Leal
authors.forename: Amy B
authors.initials: AB
authors.lastname: Emerman
authors.forename: Katherine D
authors.initials: KD
authors.lastname: Henderson
authors.forename: Elena
authors.initials: E
authors.lastname: Piskounova
authors.forename: Brian E
authors.initials: BE
authors.lastname: Henderson
authors.forename: Richard I
authors.initials: RI
authors.lastname: Gregory
authors.forename: Letícia F Gontijo
authors.initials: LF
authors.lastname: Silveira
authors.forename: Joel N
authors.initials: JN
authors.lastname: Hirschhorn
authors.forename: Thutrang T
authors.initials: TT
authors.lastname: Nguyen
authors.forename: Daiane
authors.initials: D
authors.lastname: Beneduzzi
authors.forename: Cintia
authors.initials: C
authors.lastname: Tusset
authors.forename: Ana Claudia S
authors.initials: AC
authors.lastname: Reis
authors.forename: Vinicius N
authors.initials: VN
authors.lastname: Brito
authors.forename: Berenice B
authors.initials: BB
authors.lastname: Mendonca
authors.forename: Mark R
authors.initials: MR
authors.lastname: Palmert
authors.forename: Sonir R
authors.initials: SR
authors.lastname: Antonini
authors.forename: Ana Claudia
authors.initials: AC
authors.lastname: Latronico
mesh_terms: D000293:Adolescent; D000328:Adult; D019943:Amino Acid Substitution; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics*; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D035683:MicroRNAs / Q000096:biosynthesis / Q000235:genetics; D020125:Mutation, Missense; D011629:Puberty, Precocious / Q000235:genetics* / Q000378:metabolism; D016601:RNA-Binding Proteins
chemical_list: D004268:DNA-Binding Proteins; C516326:LIN28B protein, human; D035683:MicroRNAs; D016601:RNA-Binding Proteins; C487931:mirnlet7 microRNA, human