Beck David B, Subramanian T, Vijayalingam S, Ezekiel Uthayashankar R, Donkervoort Sandra, Yang Michele L, Dubbs Holly A, Ortiz-Gonzalez Xilma R, Lakhani Shenela, Segal Devorah, Au Margaret, Graham John M, Verma Sumit, Waggoner Darrel, Shinawi Marwan, Bönnemann Carsten G, Chung Wendy K, Chinnadurai G
National Human Genome Research Institute, National Institutes of Health, 10 Center Drive, Room B3-4129, Bethesda, MD, 20892, USA.
Institute for Molecular Virology, Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, E. A. Doisy Research Center, 6th Floor, St. Louis, MO, 63104, USA.
Neurogenetics. 2019 Aug;20(3):129-143. doi: 10.1007/s10048-019-00578-1. Epub 2019 Apr 30.
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.
我们之前报道了在4名患有神经发育障碍的独立患者中，转录共抑制因子CTBP1存在致病性新生p.R342W突变[1]。在此，我们报告另外7名具有相同复发性新生CTBP1突变个体的临床表型。在这个队列中，我们确定了大多数患者中存在的与CtBP1相关的一致表型，包括智力残疾、共济失调、肌张力减退和牙釉质缺陷。CtBP1中的R342W突变位于一个与CtBP相互作用蛋白的高亲和力结合裂隙相关的区域。无偏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。在表达-CtBP1 R342（野生型）或W342突变的人胶质母细胞瘤细胞系中进行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。与对照相比，发现患者来源的皮肤成纤维细胞在急性葡萄糖剥夺期间对凋亡更敏感。葡萄糖剥夺强烈激活仅含BH3结构域的促凋亡基因NOXA，这表明患者成纤维细胞中增强的细胞死亡与NOXA表达之间存在联系。我们的结果表明，CtBP1突变体W342等位基因转录抑制的上下文依赖性缓解可能导致患者靶组织中凋亡失调，从而导致神经发育表型。
