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Abstract：
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.
摘要：
转录因子CCCTC结合因子（CTCF）中的致病变体与智力低下有关，常染色体显性21(MRD21,MIM#615502)。目前的研究支持CTCF变异与身材矮小之间的强烈关系，然而CTCF突变导致身材矮小的机制尚不清楚.临床信息,收集1例MRD21患者的治疗方案和随访结果.使用永生化淋巴细胞细胞系（LCLs）研究了CTCF变体导致身材矮小的可能致病机制，HEK-293T和永生化正常人肝细胞系(LO2)。该患者接受了重组人生长激素（rhGH）的长期治疗，导致身高增加1.0SDS。她在治疗前IGF-1水平较低，治疗期间IGF-1水平没有显着增加（-1.38±0.61SDS）。该发现表明，CTCFR567W变体可能损害了胰岛素生长因子1（IGF-1）信号通路。我们进一步证明了突变CTCF与IGF-1启动子区的结合能力降低,从而显著降低IGF-1的转录激活和表达。我们的成果初次证明了CTCF对IGF1启动子转录的直接正调控。由于CTCF突变导致的IGF-1表达受损可以解释rhGH治疗对MRD21患者的效果不佳。这项研究为CTCF相关疾病的分子基础提供了新的见解。
