MED12-Related Disease in a Chinese Girl: Clinical Characteristics and Underlying Mechanism
Chao Wang, Longlong Lin, Yan Xue, Yilin Wang, Zhao Liu, Zicheng Ou, Shengnan Wu, Xiaoping Lan, Yuanfeng Zhang, Fang Yuan, Xiaona Luo, Chunmei Wang, Jiaming Xi, Xiaomin Sun, Yucai Chen
Abstract
MED12 is a member of the mediator complex, which plays a critical role in RNA transcription. Mutations in MED12 cause X-linked intellectual disability and other anomalies collectively grouped as MED12-related disorders. While MED12 mutations have been most commonly reported in male patients, we present the case of a 1-year-old girl with clinical characteristics similar to MED12-related disorders. To explore the clinical characteristics of the condition and its possible pathogenesis, we analyzed the patient’s clinical data; genetic testing by whole-exome sequencing revealed a de novo heterozygous mutation (c.1249-1G > C) in MED12. Further cDNA experiments revealed that the patient had an abnormal splicing at the skipping of exon9, which may have produced a truncated protein. qPCR showed decreased MED12 gene expression level in the patient, and an X-chromosome inactivation test confirmed a skewed inactivation of the X-chromosome. The lymphoblast transcription levels of the genes involved in the Gli3-dependent sonic hedgehog signaling pathway, namely CREB5, BMP4, and NEUROG2, were found to be significantly elevated compared with those of her parents and sex- and age-matched controls. Our results support the view that MED12 mutations may dysregulate the Sonic hedgehog (SHH) signaling pathway, which may have accounted for the aberrant craniofacial morphology of our patient.