Department of Endocrinology, Genetics and Metabolism, Fuzhou Children's Hospital of Fujian Medical University, Fuzhou, China.
Department of Genetic and Metabolic Central Laboratory, the Maternal and Child Health Care Hospital of Guangxi Zhuang Autonomous Region, Guangxi Birth Defects Prevention and Control Institute, Nanning, China.
J Mol Endocrinol. 2023 Apr 5;70(4). doi: 10.1530/JME-22-0193. Print 2023 May 1.
Pathogenic variants in the transcription factor CCCTC-binding factor (CTCF) are associated with mental retardation, autosomal dominant 21 (MRD21, MIM#615502). Current studies supported the strong relationship between CTCF variants and growth, yet the mechanism of CTCF mutation leading to short stature is not known. Clinical information, treatment regimens, and follow-up outcomes of a patient with MRD21 were collected. The possible pathogenic mechanisms of CTCF variants leading to short stature were investigated using immortalized lymphocyte cell lines (LCLs), HEK-293T, and immortalized normal human liver cell lines (LO2). This patient received long-term treatment with recombinant human growth hormone (rhGH) which resulted in an increased height of 1.0 SDS. She had low serum insulin-like growth factor 1 (IGF1) before the treatment and the IGF1 level was not significantly increased during the treatment (-1.38 ± 0.61 SDS). The finding suggested that the CTCF R567W variant could have impaired IGF1 production pathway. We further demonstrated that the mutant CTCF had a reduced ability to bind to the promoter region of IGF1, consequently significantly reducing the transcriptional activation and expression of IGF1. Our novel results demonstrated a direct positive regulation of CTCF on the transcription of the IGF1 promoter. The impaired IGF1 expression due to CTCF mutation may explain the substandard effect of rhGH treatment on MRD21 patients. This study provided novel insights into the molecular basis of CTCF-associated disorder.
转录因子 CCCTC 结合因子 (CTCF) 的致病性变异与智力障碍、常染色体显性 21 型 (MRD21，MIM#615502) 有关。目前的研究支持 CTCF 变异与生长之间的强相关性，但 CTCF 突变导致身材矮小的机制尚不清楚。收集了一位患有 MRD21 的患者的临床信息、治疗方案和随访结果。使用永生化淋巴细胞细胞系 (LCL)、HEK-293T 和永生化正常人类肝细胞系 (LO2) 研究了 CTCF 变异导致身材矮小的可能致病机制。该患者接受了重组人生长激素 (rhGH) 的长期治疗，身高增加了 1.0 SDS。治疗前她的血清胰岛素样生长因子 1 (IGF1) 水平较低，治疗期间 IGF1 水平没有显著增加 (-1.38±0.61 SDS)。这表明 CTCF R567W 变异可能会损害 IGF1 产生途径。我们进一步表明，突变型 CTCF 与 IGF1 启动子区域的结合能力降低，从而显著降低 IGF1 的转录激活和表达。我们的新结果表明 CTCF 对 IGF1 启动子转录具有直接的正向调节作用。由于 CTCF 突变导致 IGF1 表达受损，可能解释了 rhGH 治疗对 MRD21 患者的疗效不理想。本研究为 CTCF 相关疾病的分子基础提供了新的见解。
