PITX3 mutations associated with autosomal dominant congenital cataract in the Chinese population

Wu,Zehua; Meng,Delong; Fang,Chengbo; Li,Jian; Zheng,Xiujie; Lin,Jiansuo; Zeng,Haijiang; Lv,Sihan; Zhang,Zhenning; Luan,Bing; Zhong,Zilin; Chen,Jianjun

doi:10.3892/mmr.2019.9989

PITX3 mutations associated with autosomal dominant congenital cataract in the Chinese population

Authors:
- Zehua Wu
- Delong Meng
- Chengbo Fang
- Jian Li
- Xiujie Zheng
- Jiansuo Lin
- Haijiang Zeng
- Sihan Lv
- Zhenning Zhang
- Bing Luan
- Zilin Zhong
- Jianjun Chen
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Affiliations: Department of Ophthalmology, Shanghai Tenth People's Hospital and Tongji Eye Institute, Tongji University School of Medicine, Shanghai 200092, P.R. China, Department of Ophthalmology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230032, P.R. China, Department of Endocrinology, Shanghai Tenth People's Hospital and Tongji Eye Institute, Tongji University School of Medicine, Shanghai 200092, P.R. China, Department of Pediatrics, Ganzhou People's Hospital, Ganzhou, Jiangxi 341000, P.R. China, Translational Medical Center for Stem Cell Therapy and Institute for Regenerative Medicine, Shanghai East Hospital, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Science and Technology, Tongji University, Shanghai 200092, P.R. China
Published online on: February 26, 2019 https://doi.org/10.3892/mmr.2019.9989
Pages: 3123-3131
Copyright: © Wu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

The present study aimed to identify the disease‑causing gene of a four‑generation Chinese family affected with congenital posterior subcapsular cataracts (CPSC), to additionally investigate the frequency of paired like homeodomain 3 (PITX3) mutations in Chinese patients with autosomal dominant congenital cataract (ADCC) and to analyze the pathogenesis of the mutations identified in the present study. Whole exome sequencing (WES) was utilized to identify the genetic cause of CPSC in the four‑generation family. Sanger sequencing was performed to verify the WES results and to screen for mutations of the PITX3 gene in probands of an additional 194 Chinese ADCC families. Co‑segregation analysis was performed in the family members with available DNA. Subcellular localization analyses and transactivation assays were performed for the PITX3 mutations identified. From the WES data, the c.608delC (p.A203GfsX106) mutation of PITX3 was identified in the four‑generation family with CPSC. A second PITX3 mutation c.640_656del (p.A214RfsX42) was detected in two of the additional 194 ADCC families and one of these two families exhibited incomplete penetrance. Functional studies indicated that these 2 PITX3 mutant proteins retained a nuclear localization pattern, but resulted in decreased transactivation activity, similar to other previously identified PITX3 mutations. In the present study, 2 different mutations (p.A203GfsX106 and p.A214RfsX42) in PITX3 were identified as the causative defect in a four‑generation family with CPSC and two ADCC families, respectively. The prevalence of PITX3 gene‑associated cataract was 1.54% (3/195) in the Chinese congenital cataract (CC) family cohort. In vitro functional analyses of these 2 PITX3 mutations were performed, in order to enhance understanding of the pathogenesis of CC caused by PITX3 mutations.

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