title: Novel heterozygous nonsense GLI2 mutations in patients with hypopituitarism and ectopic posterior pituitary lobe without holoprosencephaly.
abstract: BACKGROUND
  GLI2 is a transcription factor downstream in Sonic Hedgehog signaling, acting early in ventral forebrain and pituitary development. GLI2 mutations were reported in patients with holoprosencephaly (HPE) and pituitary abnormalities.
  
  
  OBJECTIVE
  The aim was to report three novel frameshift/nonsense GLI2 mutations and the phenotypic variability in the three families.
  
  
  METHODS
  The study was conducted at a university hospital.
  
  
  METHODS
  The GLI2 coding region of patients with isolated GH deficiency (IGHD) or combined pituitary hormone deficiency was amplified by PCR using intronic primers and sequenced.
  
  
  RESULTS
  Three novel heterozygous GLI2 mutations were identified: c.2362_2368del p.L788fsX794 (family 1), c.2081_2084del p.L694fsX722 (family 2), and c.1138 G>T p.E380X (family 3). All predict a truncated protein with loss of the C-terminal activator domain. The index case of family 1 had polydactyly, hypoglycemia, and seizures, and GH, TSH, prolactin, ACTH, LH, and FSH deficiencies. Her mother and seven relatives harboring the same mutation had polydactyly, including two uncles with IGHD and one cousin with GH, TSH, LH, and FSH deficiencies. In family 2, a boy had cryptorchidism, cleft lip and palate, and GH deficiency. In family 3, a girl had hypoglycemia, seizures, excessive thirst and polyuria, and GH, ACTH, TSH, and antidiuretic hormone deficiencies. Magnetic resonance imaging of four patients with GLI2 mutations and hypopituitarism showed a hypoplastic anterior pituitary and an ectopic posterior pituitary lobe without HPE.
  
  
  CONCLUSIONS
  We describe three novel heterozygous frameshift or nonsense GLI2 mutations, predicting truncated proteins lacking the activator domain, associated with IGHD or combined pituitary hormone deficiency and ectopic posterior pituitary lobe without HPE. These phenotypes support partial penetrance, variable polydactyly, midline facial defects, and pituitary hormone deficiencies, including diabetes insipidus, conferred by heterozygous frameshift or nonsense GLI2 mutations.
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 São Paulo, São 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: Gabriela A
authors.initials: GA
authors.lastname: Vasques
authors.forename: Claudia C
authors.initials: CC
authors.lastname: Leite
authors.forename: Berenice B
authors.initials: BB
authors.lastname: Mendonca
authors.forename: Ivo J P
authors.initials: IJ
authors.lastname: Arnhold
mesh_terms: D002648:Child; D002828:Choristoma / Q000235:genetics / Q000473:pathology; D018389:Codon, Nonsense; D005260:Female; D016142:Holoprosencephaly / Q000235:genetics*; D006801:Humans; D007018:Hypopituitarism / Q000235:genetics* / Q000473:pathology; D051741:Kruppel-Like Transcription Factors / Q000235:genetics*; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009687:Nuclear Proteins / Q000235:genetics*; D010375:Pedigree; D010904:Pituitary Gland, Posterior / Q000473:pathology*; D000075746:Zinc Finger Protein Gli2
chemical_list: D018389:Codon, Nonsense; C082593:GLI2 protein, human; D051741:Kruppel-Like Transcription Factors; D009687:Nuclear Proteins; D000075746:Zinc Finger Protein Gli2