Gregory L C, Gaston-Massuet C, Andoniadou C L, Carreno G, Webb E A, Kelberman D, McCabe M J, Panagiotakopoulos L, Saldanha J W, Spoudeas H A, Torpiano J, Rossi M, Raine J, Canham N, Martinez-Barbera J P, Dattani M T
Genetics and Epigenetics in Health and Disease Section, Genetics and Genomic Medicine Programme, UCL Institute of Child Health, London, UK.
Clin Endocrinol (Oxf). 2015 May;82(5):728-38. doi: 10.1111/cen.12637. Epub 2014 Dec 9.
The Gli family of zinc finger (GLI) transcription factors mediates the sonic hedgehog signalling pathway (HH) essential for CNS, early pituitary and ventral forebrain development in mice. Human mutations in this pathway have been described in patients with holoprosencephaly (HPE), isolated congenital hypopituitarism (CH) and cranial/midline facial abnormalities. Mutations in Sonic hedgehog (SHH) have been associated with HPE but not CH, despite murine studies indicating involvement in pituitary development.
OBJECTIVES/METHODS: We aimed to establish the role of the HH pathway in the aetiology of hypothalamo-pituitary disorders by screening our cohort of patients with midline defects and/or CH for mutations in SHH, GLI2, Shh brain enhancer 2 (SBE2) and growth-arrest specific 1 (GAS1).
Two variants and a deletion of GLI2 were identified in three patients. A novel variant at a highly conserved residue in the zinc finger DNA-binding domain, c.1552G > A [pE518K], was identified in a patient with growth hormone deficiency and low normal free T4. A nonsynonymous variant, c.2159G > A [p.R720H], was identified in a patient with a short neck, cleft palate and hypogonadotrophic hypogonadism. A 26·6 Mb deletion, 2q12·3-q21·3, encompassing GLI2 and 77 other genes, was identified in a patient with short stature and impaired growth. Human embryonic expression studies and molecular characterisation of the GLI2 mutant p.E518K support the potential pathogenicity of GLI2 mutations. No mutations were identified in GAS1 or SBE2. A novel SHH variant, c.1295T>A [p.I432N], was identified in two siblings with variable midline defects but normal pituitary function.
Our data suggest that mutations in SHH, GAS1 and SBE2 are not associated with hypopituitarism, although GLI2 is an important candidate for CH.
锌指（GLI）转录因子家族介导了小鼠中枢神经系统、早期垂体和腹侧前脑发育所必需的音猬因子信号通路（HH）。该通路中的人类突变已在全前脑畸形（HPE）、孤立性先天性垂体功能减退（CH）和颅面/中线面部异常患者中被描述。尽管小鼠研究表明音猬因子（SHH）参与垂体发育，但SHH突变与HPE相关，而与CH无关。
目的/方法：我们旨在通过筛查中线缺陷和/或CH患者队列中的SHH、GLI2、音猬因子脑增强子2（SBE2）和生长停滞特异性蛋白1（GAS1）突变，来确定HH通路在下丘脑 - 垂体疾病病因中的作用。
在三名患者中鉴定出两个变异和一个GLI2缺失。在一名生长激素缺乏且游离T4处于低正常水平的患者中，在锌指DNA结合结构域的一个高度保守残基处鉴定出一个新变异，c.1552G > A [pE518K]。在一名颈部短、腭裂和低促性腺激素性性腺功能减退的患者中鉴定出一个非同义变异，c.2159G > A [p.R720H]。在一名身材矮小且生长受损的患者中鉴定出一个26.6 Mb的缺失，2q12.3 - q21.3，包含GLI2和其他77个基因。人类胚胎表达研究和GLI2突变体p.E518K的分子特征支持GLI2突变的潜在致病性。在GAS1或SBE2中未鉴定出突变。在两名中线缺陷各异但垂体功能正常的兄弟姐妹中鉴定出一个新的SHH变异，c.1295T > A [p.I432N]。
我们的数据表明，SHH、GAS1和SBE2突变与垂体功能减退无关，尽管GLI2是CH的一个重要候选基因。
