title: Relatively high frequency of non-synonymous GLI2 variants in patients with congenital hypopituitarism without holoprosencephaly.
abstract: OBJECTIVE
  GLI2 is a downstream transcription factor in Sonic Hedgehog signalling, acting early in ventral forebrain and pituitary development. Heterozygous nonsense GLI2 mutations have been reported in patients with isolated or combined pituitary hormone deficiency (CPHD), with or without holoprosencephaly. The aim of this study was to screen for GLI2 mutations in a large cohort of patients with congenital GH deficiency.
  
  
  METHODS
  The GLI2 coding region of 41 patients with severe isolated GH deficiency (IGHD) and 136 patients with CPHD was amplified by PCR using intronic primers and sequenced. The frequency of GLI2 variants was verified in up to 155 Brazilian controls and in the 1000 Genomes database. The consequences of allelic variants were analysed by the Polyphen, SIFT, Mutationtaster and SNAP prediction sites.
  
  
  RESULTS
  Eighteen different heterozygous non-synonymous GLI2 variants were identified in 24 patients. Twenty-three patients had CPHD and one had IGHD. Two patients had additional diabetes insipidus, indicating deficiencies of anterior and posterior pituitary lobes. The posterior pituitary lobe on MRI was ectopic in 16, not visible in 4, normally placed in 2 and imaging was not available in two patients, but there were no signs of holoprosencephaly. Sixteen GLI2 variants were considered deleterious in at least one of the prediction sites.
  
  
  CONCLUSIONS
  A relatively high frequency of non-synonymous GLI2 variants was identified in patients with congenital GH deficiency without other brain defects, and most of these patients presented with CPHD and an ectopic posterior pituitary lobe. In vitro functional assays may contribute to ascertain the deleterious consequences of these variants.
authors.affiliation: Unidade de Endocrinologia do Desenvolvimento, Laboratorio de Hormonios e Genetica Molecular LIM/42, Disciplina de Endocrinologia, Hospital das Clinicas da Faculdade de Medicina da Universidade de Sao Paulo, Sao Paulo, Brazil.
authors.forename: Marcela M
authors.initials: MM
authors.lastname: França
authors.forename: Alexander A L
authors.initials: AA
authors.lastname: Jorge
authors.forename: Luciani R S
authors.initials: LR
authors.lastname: Carvalho
authors.forename: Everlayny F
authors.initials: EF
authors.lastname: Costalonga
authors.forename: Aline P
authors.initials: AP
authors.lastname: Otto
authors.forename: Fernanda A
authors.initials: FA
authors.lastname: Correa
authors.forename: Berenice B
authors.initials: BB
authors.lastname: Mendonca
authors.forename: Ivo J P
authors.initials: IJ
authors.lastname: Arnhold
mesh_terms: D000293:Adolescent; D000328:Adult; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D005260:Female; D005787:Gene Frequency; D016142:Holoprosencephaly / Q000235:genetics; D019382:Human Growth Hormone / Q000172:deficiency; D006801:Humans; D007018:Hypopituitarism / Q000151:congenital* / Q000235:genetics*; D007223:Infant; D051741:Kruppel-Like Transcription Factors / Q000235:genetics*; D008297:Male; D020125:Mutation, Missense; D009687:Nuclear Proteins / Q000235:genetics*; D055815:Young Adult; D000075746:Zinc Finger Protein Gli2
chemical_list: C082593:GLI2 protein, human; D051741:Kruppel-Like Transcription Factors; D009687:Nuclear Proteins; D000075746:Zinc Finger Protein Gli2; D019382:Human Growth Hormone