title: Cosegregation of a novel mutation in the sixth transmembrane segment of the luteinizing/choriogonadotropin hormone receptor with two Brazilian siblings with severe testotoxicosis.
abstract: OBJECTIVE
  Testotoxicosis is an autosomal dominant form of gonadotropin-independent precocious puberty caused by heterozygous constitutively activating mutations of the luteinizing hormone/choriogonadotropin receptor (LHCGR) gene. The aim of this study was to describe two Brazilian siblings with testotoxicosis, to confirm the molecular diagnosis, and to perform an in silico analysis of a novel mutation in the hot spot of the LHCGR gene.
  
  
  METHODS
  Molecular analysis of the mutation on the LHCGR gene was performed by direct Sanger sequencing, followed by an in silico analysis using HOPE bioinformatics tool to predict a functional defect of the mutant.
  
  
  RESULTS
  Both patients presented with gonadotropin-independent precocious puberty before the age of four years. Genetic analysis revealed a novel non-maternally inherited p.Asp578Val mutation of the LHCGR gene. An in silico analysis showed that the p.Asp578Val mutation disturbed amino acid physicochemical features regarding its size, charge, and hydrophobicity value.
  
  
  CONCLUSIONS
  Clinical and hormonal profile of the siblings here evaluated was not different while compared to those patients previously described. An in silico mutation analysis reinforced the causative role of recurrent activating mutations in the intracellular loop and transmembrane helices of the LHCGR. The segregation of this mutation with the offsprings' phenotype indicated that it is causative.
authors.affiliation: a Division of Pediatric Endocrinology, Department of Pediatrics , Federal University of Sao Paulo - UNIFESP/EPM , Sao Paulo , Brazil.
authors.forename: Adriana A
authors.initials: AA
authors.lastname: Siviero-Miachon
authors.affiliation: b Laboratory of Molecular and Translational Endocrinology, Department of Medicine , Federal University of Sao Paulo , Sao Paulo , Brazil.
authors.forename: Marina M L
authors.initials: MM
authors.lastname: Kizys
authors.affiliation: a Division of Pediatric Endocrinology, Department of Pediatrics , Federal University of Sao Paulo - UNIFESP/EPM , Sao Paulo , Brazil.
authors.forename: Manuela M
authors.initials: MM
authors.lastname: Ribeiro
authors.affiliation: a Division of Pediatric Endocrinology, Department of Pediatrics , Federal University of Sao Paulo - UNIFESP/EPM , Sao Paulo , Brazil.
authors.forename: Fabiola Esgrignoli
authors.initials: FE
authors.lastname: Garcia
authors.affiliation: a Division of Pediatric Endocrinology, Department of Pediatrics , Federal University of Sao Paulo - UNIFESP/EPM , Sao Paulo , Brazil.
authors.forename: Angela M
authors.initials: AM
authors.lastname: Spinola-Castro
authors.affiliation: b Laboratory of Molecular and Translational Endocrinology, Department of Medicine , Federal University of Sao Paulo , Sao Paulo , Brazil.
authors.forename: Magnus R
authors.initials: MR
authors.lastname: Dias da Silva
mesh_terms: D000293:Adolescent; D001938:Brazil; D002648:Child; D006801:Humans; D008297:Male; D009154:Mutation; D011629:Puberty, Precocious / Q000235:genetics*; D011974:Receptors, LH / Q000235:genetics*; D035781:Siblings
chemical_list: D011974:Receptors, LH
keywords: In silico analysis; LH; luteinizing hormone; precocious; puberty; receptors