title: Role of GLI2 in hypopituitarism phenotype.
abstract: GLI2 is a zinc-finger transcription factor involved in the Sonic Hedgehog pathway. Gli2 mutant mice have hypoplastic anterior and absent posterior pituitary glands. We reviewed the literature for patients with hypopituitarism and alterations in GLI2. Twenty-five patients (16 families) had heterozygous truncating mutations, and the phenotype frequently included GH deficiency, a small anterior pituitary lobe and an ectopic/undescended posterior pituitary lobe on magnetic resonance imaging and postaxial polydactyly. The inheritance pattern was autosomal dominant with incomplete penetrance and variable expressivity. The mutation was frequently inherited from an asymptomatic parent. Eleven patients had heterozygous non-synonymous GLI2 variants that were classified as variants of unknown significance, because they were either absent from or had a frequency lower than 0.001 in the databases. In these patients, the posterior pituitary was also ectopic, but none had polydactyly. A third group of variants found in patients with hypopituitarism were considered benign because their frequency was ≥ 0.001 in the databases. GLI2 is a large and polymorphic gene, and sequencing may identify variants whose interpretation may be difficult. Incomplete penetrance implies in the participation of other genetic and/or environmental factors. An interaction between Gli2 mutations and prenatal ethanol exposure has been demonstrated in mice dysmorphology. In conclusion, a relatively high frequency of GLI2 mutations and variants were identified in patients with congenital GH deficiency without other brain defects, and most of these patients presented with combined pituitary hormone deficiency and an ectopic posterior pituitary lobe. Future studies may clarify the relative role and frequency of GLI2 alterations in the aetiology of hypopituitarism.
authors: Divisão de EndocrinologiaUnidade de Endocrinologia do Desenvolvimento, Laboratorio de Hormonios e Genetica Molecular LIM/42, Hospital das Clinicas da FMUSP, Disciplina de Endocrinologia da Faculdade de Medicina da Universidade de Sao Paulo, Avenida Eneas de Carvalho Aguiar, 155, Prédio dos Ambulatórios, 8° andar, Bloco 3, CEP 05403-900 Sao Paulo, BrazilUnidade de Endocrinologia GeneticaLaboratorio de Endocrinologia Celular e Molecular LIM/25, Disciplina de Endocrinologia da Faculdade de Medicina da Universidade de Sao Paulo, 01246-903 Sao Paulo, Brazil iarnhold@usp.br.
authors: Ivo J P
authors: IJ
authors: Arnhold
authors: Divisão de EndocrinologiaUnidade de Endocrinologia do Desenvolvimento, Laboratorio de Hormonios e Genetica Molecular LIM/42, Hospital das Clinicas da FMUSP, Disciplina de Endocrinologia da Faculdade de Medicina da Universidade de Sao Paulo, Avenida Eneas de Carvalho Aguiar, 155, Prédio dos Ambulatórios, 8° andar, Bloco 3, CEP 05403-900 Sao Paulo, BrazilUnidade de Endocrinologia GeneticaLaboratorio de Endocrinologia Celular e Molecular LIM/25, Disciplina de Endocrinologia da Faculdade de Medicina da Universidade de Sao Paulo, 01246-903 Sao Paulo, Brazil.
authors: Marcela M
authors: MM
authors: França
authors: Divisão de EndocrinologiaUnidade de Endocrinologia do Desenvolvimento, Laboratorio de Hormonios e Genetica Molecular LIM/42, Hospital das Clinicas da FMUSP, Disciplina de Endocrinologia da Faculdade de Medicina da Universidade de Sao Paulo, Avenida Eneas de Carvalho Aguiar, 155, Prédio dos Ambulatórios, 8° andar, Bloco 3, CEP 05403-900 Sao Paulo, BrazilUnidade de Endocrinologia GeneticaLaboratorio de Endocrinologia Celular e Molecular LIM/25, Disciplina de Endocrinologia da Faculdade de Medicina da Universidade de Sao Paulo, 01246-903 Sao Paulo, Brazil.
authors: Luciani R
authors: LR
authors: Carvalho
authors: Divisão de EndocrinologiaUnidade de Endocrinologia do Desenvolvimento, Laboratorio de Hormonios e Genetica Molecular LIM/42, Hospital das Clinicas da FMUSP, Disciplina de Endocrinologia da Faculdade de Medicina da Universidade de Sao Paulo, Avenida Eneas de Carvalho Aguiar, 155, Prédio dos Ambulatórios, 8° andar, Bloco 3, CEP 05403-900 Sao Paulo, BrazilUnidade de Endocrinologia GeneticaLaboratorio de Endocrinologia Celular e Molecular LIM/25, Disciplina de Endocrinologia da Faculdade de Medicina da Universidade de Sao Paulo, 01246-903 Sao Paulo, Brazil.
authors: Berenice B
authors: BB
authors: Mendonca
authors: Divisão de EndocrinologiaUnidade de Endocrinologia do Desenvolvimento, Laboratorio de Hormonios e Genetica Molecular LIM/42, Hospital das Clinicas da FMUSP, Disciplina de Endocrinologia da Faculdade de Medicina da Universidade de Sao Paulo, Avenida Eneas de Carvalho Aguiar, 155, Prédio dos Ambulatórios, 8° andar, Bloco 3, CEP 05403-900 Sao Paulo, BrazilUnidade de Endocrinologia GeneticaLaboratorio de Endocrinologia Celular e Molecular LIM/25, Disciplina de Endocrinologia da Faculdade de Medicina da Universidade de Sao Paulo, 01246-903 Sao Paulo, Brazil.
authors: Alexander A L
authors: AA
authors: Jorge
mesh_terms: D000818:Animals; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D007018:Hypopituitarism / Q000235:genetics* / Q000378:metabolism; D051741:Kruppel-Like Transcription Factors / Q000502:physiology*; D009154:Mutation; D009687:Nuclear Proteins / Q000502:physiology*; D010641:Phenotype; D010902:Pituitary Gland / Q000196:embryology; D015398:Signal Transduction; D000075746:Zinc Finger Protein Gli2
chemical_list: C082593:GLI2 protein, human; D051741:Kruppel-Like Transcription Factors; D009687:Nuclear Proteins; D000075746:Zinc Finger Protein Gli2
keywords: GLI2; growth; hypopituitarism; mutations