We previously reported a pathogenic de novo p.R342W mutation in the transcriptional corepressor CTBP1 in four independent patients with neurodevelopmental disabilities [1]. Here, we report the clinical phenotypes of seven additional individuals with the same recurrent de novo CTBP1 mutation. Within this cohort, we identified consistent CtBP1-related phenotypes of intellectual disability, ataxia, hypotonia, and tooth enamel defects present in most patients. The R342W mutation in CtBP1 is located within a region implicated in a high affinity-binding cleft for CtBP-interacting proteins. Unbiased proteomic analysis demonstrated reduced interaction of several chromatin-modifying factors with the CtBP1 W342 mutant. Genome-wide transcriptome analysis in human glioblastoma cell lines expressing -CtBP1 R342 (wt) or W342 mutation revealed changes in the expression profiles of genes controlling multiple cellular processes. Patient-derived dermal fibroblasts were found to be more sensitive to apoptosis during acute glucose deprivation compared to controls. Glucose deprivation strongly activated the BH3-only pro-apoptotic gene NOXA, suggesting a link between enhanced cell death and NOXA expression in patient fibroblasts. Our results suggest that context-dependent relief of transcriptional repression of the CtBP1 mutant W342 allele may contribute to deregulation of apoptosis in target tissues of patients leading to neurodevelopmental phenotypes.

中文翻译：

---

致病性CtBP1错义突变导致辅因子结合和转录活性改变。

我们先前曾报道四名神经发育障碍独立患者的转录共抑制因子CTBP1中有一个致病性新生p.R342W突变[1]。在这里，我们报告了另外7例具有相同复发性从头CTBP1的个体的临床表型突变。在该队列中，我们确定了大多数患者中存在的与智力障碍，共济失调，肌张力低下和牙釉质缺损相关的CtBP1相关表型。CtBP1中的R342W突变位于与CtBP相互作用蛋白的高亲和力结合裂隙相关的区域内。公正的蛋白质组学分析表明，几种染色质修饰因子与CtBP1 W342突变体的相互作用减少。表达-CtBP1 R342（wt）或W342突变的人胶质母细胞瘤细胞系中的全基因组转录组分析揭示了控制多个细胞过程的基因表达谱的变化。与对照组相比，在急性葡萄糖剥夺过程中发现患者来源的真皮成纤维细胞对凋亡更敏感。葡萄糖剥夺强烈激活仅BH3促凋亡基因NOXA，提示患者成纤维细胞的细胞死亡增强与NOXA表达之间存在联系。我们的结果表明，上下文依赖的CtBP1突变体W342等位基因转录抑制的缓解可能有助于导致神经发育表型的患者靶组织中凋亡的失调。