Molecular Neurobiology Laboratory, Division of Neuroscience, IRCSS San Raffaele Scientific Institute, Milan, Italy.
Centre for Translational Genomics and Bioinformatics, IRCSS San Raffaele Scientific Institute, Milan, Italy.
PLoS One. 2019 Jan 10;14(1):e0210097. doi: 10.1371/journal.pone.0210097. eCollection 2019.
GLI2 encodes for a transcription factor that controls the expression of several genes in the Hedgehog pathway. Mutations in GLI2 have been described as causative of a spectrum of clinical phenotypes, notably holoprosencephaly, hypopituitarism and postaxial polydactyl.
In order to identify causative genetic variant, we performed exome sequencing of a trio from an Italian family with multiple affected individuals presenting clinical phenotypes in the Culler-Jones syndrome spectrum. We performed a series of cell-based assays to test the functional properties of mutant GLI2.
Here we report a novel deletion c.3493delC (p.P1167LfsX52) in the C-terminal activation domain of GLI2. Functional assays confirmed the pathogenicity of the identified variant and revealed a dominant-negative effect of mutant GLI2 on Hedgehog signalling.
Our results highlight the variable clinical manifestation of GLI2 mutations and emphasize the value of functional characterisation of novel gene variants to assist genetic counselling and diagnosis.
GLI2 基因编码转录因子，可控制 Hedgehog 通路中多个基因的表达。GLI2 基因突变已被描述为多种临床表型的致病原因，特别是前脑无裂畸形、垂体功能减退和后轴多指。
为了鉴定致病的遗传变异，我们对一个意大利家族的三人组进行了外显子组测序，该家族有多个受影响的个体，表现出 Culler-Jones 综合征谱中的临床表型。我们进行了一系列基于细胞的实验来测试突变 GLI2 的功能特性。
我们在这里报告了 GLI2 中 C 末端激活结构域的新型缺失 c.3493delC（p.P1167LfsX52）。功能实验证实了所鉴定变异的致病性，并揭示了突变 GLI2 对 Hedgehog 信号的显性负效应。
我们的结果强调了 GLI2 突变的可变临床表现，并强调了对新型基因突变进行功能特征分析以辅助遗传咨询和诊断的重要性。
