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Hong Chen, Weiyu Li, Suping Zhang, Yunteng Sun, Yiping Shen, and Ruimin Chen

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 short stature, 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 a long-term treatment with recombinant human growth hormone (rhGH) and resulted in an increased height of 1.0 SDS. She had low IGF-1 levels before the treatment and the IGF-1 level was not significantly increased during the treatment (-1.38±0.61 SDS). The finding suggested that the CTCFR567W variant could have impaired the insulin growth factors 1 (IGF-1) signaling pathway. We further demonstrated that the mutant CTCF had a reduced ability binding to the promoter region of IGF-1, consequently significantly reducing the transcriptional activation and expression of IGF-1. Our results demonstrated a direct positive regulation of CTCF on the transcription of the IGF1 promoter for the first time. The impaired IGF-1 expression due to CTCF mutation could explain the poor effect of rhGH treatment on MRD21 patients. This study provided novel insights to the molecular basis of CTCF associated disorder.