ResearchIn-Press PreviewGeneticsOphthalmology Open Access | 10.1172/jci.insight.177032
1MOE Key Lab of Rare Pediatric Diseases & Hunan Key Laboratory of Medical Ge, Central South University, Changsha, China
2Department of Medical Genetics, The Affiliated Children's Hospital of Xiang, Central South University, Hunan Children's Hospital, Changsha, China
3Department of Ophthalmology, The Second Xiangya Hospital, Central South University, Changsha, China
Find articles by Jiang, Y. in: JCI | PubMed | Google Scholar
1MOE Key Lab of Rare Pediatric Diseases & Hunan Key Laboratory of Medical Ge, Central South University, Changsha, China
2Department of Medical Genetics, The Affiliated Children's Hospital of Xiang, Central South University, Hunan Children's Hospital, Changsha, China
3Department of Ophthalmology, The Second Xiangya Hospital, Central South University, Changsha, China
Find articles by Peng, Y. in: JCI | PubMed | Google Scholar |
1MOE Key Lab of Rare Pediatric Diseases & Hunan Key Laboratory of Medical Ge, Central South University, Changsha, China
2Department of Medical Genetics, The Affiliated Children's Hospital of Xiang, Central South University, Hunan Children's Hospital, Changsha, China
3Department of Ophthalmology, The Second Xiangya Hospital, Central South University, Changsha, China
Find articles by Tian, Q. in: JCI | PubMed | Google Scholar
1MOE Key Lab of Rare Pediatric Diseases & Hunan Key Laboratory of Medical Ge, Central South University, Changsha, China
2Department of Medical Genetics, The Affiliated Children's Hospital of Xiang, Central South University, Hunan Children's Hospital, Changsha, China
3Department of Ophthalmology, The Second Xiangya Hospital, Central South University, Changsha, China
Find articles by Cheng, Z. in: JCI | PubMed | Google Scholar
1MOE Key Lab of Rare Pediatric Diseases & Hunan Key Laboratory of Medical Ge, Central South University, Changsha, China
2Department of Medical Genetics, The Affiliated Children's Hospital of Xiang, Central South University, Hunan Children's Hospital, Changsha, China
3Department of Ophthalmology, The Second Xiangya Hospital, Central South University, Changsha, China
Find articles by Feng, B. in: JCI | PubMed | Google Scholar
1MOE Key Lab of Rare Pediatric Diseases & Hunan Key Laboratory of Medical Ge, Central South University, Changsha, China
2Department of Medical Genetics, The Affiliated Children's Hospital of Xiang, Central South University, Hunan Children's Hospital, Changsha, China
3Department of Ophthalmology, The Second Xiangya Hospital, Central South University, Changsha, China
Find articles by Hu, J. in: JCI | PubMed | Google Scholar
1MOE Key Lab of Rare Pediatric Diseases & Hunan Key Laboratory of Medical Ge, Central South University, Changsha, China
2Department of Medical Genetics, The Affiliated Children's Hospital of Xiang, Central South University, Hunan Children's Hospital, Changsha, China
3Department of Ophthalmology, The Second Xiangya Hospital, Central South University, Changsha, China
Find articles by Xia, L. in: JCI | PubMed | Google Scholar
1MOE Key Lab of Rare Pediatric Diseases & Hunan Key Laboratory of Medical Ge, Central South University, Changsha, China
2Department of Medical Genetics, The Affiliated Children's Hospital of Xiang, Central South University, Hunan Children's Hospital, Changsha, China
3Department of Ophthalmology, The Second Xiangya Hospital, Central South University, Changsha, China
Find articles by Guo, H. in: JCI | PubMed | Google Scholar |
1MOE Key Lab of Rare Pediatric Diseases & Hunan Key Laboratory of Medical Ge, Central South University, Changsha, China
2Department of Medical Genetics, The Affiliated Children's Hospital of Xiang, Central South University, Hunan Children's Hospital, Changsha, China
3Department of Ophthalmology, The Second Xiangya Hospital, Central South University, Changsha, China
Find articles by Xia, K. in: JCI | PubMed | Google Scholar
1MOE Key Lab of Rare Pediatric Diseases & Hunan Key Laboratory of Medical Ge, Central South University, Changsha, China
2Department of Medical Genetics, The Affiliated Children's Hospital of Xiang, Central South University, Hunan Children's Hospital, Changsha, China
3Department of Ophthalmology, The Second Xiangya Hospital, Central South University, Changsha, China
Find articles by Zhou, L. in: JCI | PubMed | Google Scholar
1MOE Key Lab of Rare Pediatric Diseases & Hunan Key Laboratory of Medical Ge, Central South University, Changsha, China
2Department of Medical Genetics, The Affiliated Children's Hospital of Xiang, Central South University, Hunan Children's Hospital, Changsha, China
3Department of Ophthalmology, The Second Xiangya Hospital, Central South University, Changsha, China
Find articles by Hu, Z. in: JCI | PubMed | Google Scholar |
Published April 9, 2024 - More info
Recent studies have uncovered that non-coding sequence variants may relate to Axenfeld-Rieger syndrome (ARS), a rare developmental anomaly with genetic heterogeneity. However, how these genomic regions are functionally and structurally associated with ARS is still unclear. In this study, we performed genome-wide linkage analysis and whole-genome sequencing in a Chinese ARS family and identified a heterozygous deletion of about 570 kb (termed LOH-1) in the intergenic sequence between PITX2 and FAM241A. Knockout of LOH-1 homologous sequences caused ARS phenotypes in mice. RNA-seq and RT-qPCR revealed a significant reduction in Pitx2 gene expression in LOH-1–/– mice, while Foxc1 expression remained unchanged. ChIP-seq and bioinformatics analysis identified a potential enhancer region (LOH-E1) within LOH-1. Deletion of LOH-E1 led to a significant downregulation of the PITX2 gene. Mechanistically, we found a sequence (hg38 chr4:111,399,594-111,399,691) which is on LOH-E1 could regulate PITX2 by binding to RAD21, a critical component of the cohesin complex. Knockdown of RAD21 resulted in reduced PITX2 expression. Collectively, our findings indicate that a potential enhancer sequence which is within LOH-1 may regulate PITX2 expression remotely through cohesin-mediated loop domains, leading to ARS when absent. 2