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.
Clin Endocrinol (Oxf). 2013 Apr;78(4):551-7. doi: 10.1111/cen.12044.
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.
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.
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.
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.
GLI2 是 Sonic Hedgehog 信号通路中的下游转录因子，在腹侧前脑和垂体发育的早期起作用。已有报道称，杂合性无义 GLI2 突变与孤立或联合垂体激素缺乏症（CPHD）有关，这些患者可能存在或不存在全前脑畸形。本研究旨在对大量先天性生长激素缺乏症（IGHD）患者进行 GLI2 突变筛查。
使用内含子引物通过 PCR 扩增 41 例严重孤立性 GH 缺乏症（IGHD）和 136 例 CPHD 患者的 GLI2 编码区，并进行测序。在多达 155 名巴西对照和 1000 基因组数据库中验证 GLI2 变异体的频率。通过 Polyphen、SIFT、Mutationtaster 和 SNAP 预测网站分析等位基因变异的后果。
在 24 名患者中发现了 18 种不同的杂合性非同义 GLI2 变异体。23 名患者患有 CPHD，1 名患者患有 IGHD。2 名患者同时患有尿崩症，表明存在前垂体和后垂体叶的缺陷。MRI 显示 16 名患者的后垂体叶异位，4 名患者的后垂体叶不可见，2 名患者的后垂体叶位置正常，另外 2 名患者的后垂体叶影像学资料不可用，但均无全前脑畸形的迹象。在至少一个预测位点中，16 种 GLI2 变异体被认为具有有害影响。
在没有其他脑缺陷的先天性 GH 缺乏症患者中，发现了相对较高频率的非同义 GLI2 变异体，其中大多数患者表现为 CPHD 和异位的后垂体叶。体外功能测定可能有助于确定这些变异体的有害后果。
