New Discovery: Study on the Association between GJA8 Gene Mutations and Familial Aniridia-Microphthalmia-Cataract Syndrome

Research Background

Normal eye development is a process that requires the coordinated action of multiple genes and factors. Abnormal eye development can lead to congenital eye malformations such as anophthalmia, microphthalmia, or coloboma. Congenital aniridia is a rare disease characterized by the absence of pupils in the eyes. To date, only one family and two isolated cases of this condition have been reported. The genes associated with aniridia have not been identified, leading to unclear pathogenesis. To address this scientific question, this study recruited a Chinese family with congenital aniridia-microphthalmia-cataract syndrome, aiming to reveal the underlying genetic factors of this hereditary disease.

Paper Source

This research paper was jointly completed by Dongqusheng, Zou Tongdan, Zhen Fangyuan, Wang Ting, Zhou Yongwei, Wu Jiahui, Osada Tatsuo, Matsushita Gen, Gong Bo, Kondo Hiroyuki, Li Qiuming, and Zhang Houbin, affiliated with institutions including the Department of Ophthalmology, First Affiliated Hospital of Zhengzhou University, Department of Experimental Medicine, Sichuan Provincial People’s Hospital, and Department of Ophthalmology, University of Occupational and Environmental Health, Japan. The research findings were published in the European Journal of Human Genetics in 2024, with the article DOI: 10.1038/s41431-023-01503-9.

Research Process

The study followed the following process:

1. Case selection: Recruited a Chinese family and a previously reported Japanese family with patients presenting symptoms of aniridia, microphthalmia, and cataract syndrome, with an autosomal dominant inheritance pattern.
2. Whole Exome Sequencing (WES): Performed whole exome sequencing analysis on the genomic DNA of the above families to screen for disease-related genetic variants.
3. Sanger sequencing verification: Verified the identified candidate variants through Sanger sequencing.

The study identified two heterozygous mutations associated with the syndrome: c.137G>A (p.G46E) and c.151G>A (p.D51N) in the GJA8 gene.

Main Research Findings

1. A novel heterozygous mutation c.137G>A (p.G46E) was discovered in the Chinese family, while another homologous mutation c.151G>A (p.D51N) was found in the Japanese family. These two mutations co-segregated with the syndrome in unrelated families.
2. In vitro expression of the mutations led to abnormal protein expression in cultured cells, indicating that these two mutations disrupt the function of gap junction channels.
3. Bioinformatics analysis of the c.137G>A (p.G46E) and c.151G>A (p.D51N) variants showed that they are located in highly conserved regions of the CX50 protein.
4. GJA8 is the first gene associated with familial aniridia-microphthalmia-cataract syndrome.

Research Conclusions and Significance

The study found that the c.137G>A (p.G46E) and c.151G>A (p.D51N) variants in the GJA8 gene are associated with this rare syndrome. This is the first time that the GJA8 gene has been linked to aniridia syndrome, expanding the spectrum of variants and symptoms associated with this gene. This discovery provides new clues for further elucidating the etiology of congenital aniridia, microphthalmia, and cataract syndrome, with important implications for clinical diagnosis and treatment.

Research Highlights

The highlights of this study include:

• Revealing previously unknown associations between genes and rare eye diseases.
• Providing a rich spectrum of mutations, including a novel heterozygous mutation that had not been reported before.
• Enhancing understanding of the genetic mechanisms of familial diseases through systematic genomic analysis and comprehensive evaluation of clinical data.

Other Important Information

The detailed description of research methodology and case sources demonstrates the rigor of the study design and the reliability of the data, validating the practical value of advanced technologies such as whole exome sequencing in studying the genetic mechanisms of rare diseases.