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Association of variants in GJA8 with familial acorea-microphthalmia-cataract syndrome

European Journal of Human Genetics volume 32, pages 413–420 (2024)Cite this article

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Abstract

Congenital acorea is a rare disease with the absence of a pupil in the eye. To date, only one family and two isolated cases with congenital acorea have been reported. The gene associated with acorea has not been identified. In this study, we recruited a Chinese family acorea-microphthalmia-cataract syndrome. By analyzing the whole-exome sequencing (WES) data of this Chinese family, we revealed the association of a novel heterozygous variant, NM_005267.5:c.137G>A (p.G46E) in the gap junction protein alpha 8 (GJA8) gene encoding connexin 50 or CX50, with familial acorea-microphthalmia-cataract syndrome. Additionally, another variant, NM_005267.5:c.151G>A (p.D51N) in GJA8, was identified to co-segregate with this syndrome in an unrelated Japanese family. Ectopic expression of p.G46E and p.D51N mutant GJA8 genes in cultured cells caused protein mislocalization, suggesting that the p.G46E and p.D51N mutations in GJA8 impaired the function of the gap junction channels. These results established GJA8 as the first gene associated with familial acorea-microphthalmia-cataract syndrome.

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Fig. 1: Pedigrees of the Chinese and Japanese families with congenital acorea, microphthalmia, and cataract syndrome.
Fig. 2: Slit-lamp photographs, B-scan ultrasonography, fundus photography, and ultrasound biomicroscopy.
Fig. 3: Validation of the variant in GJA8 by Sanger sequencing.
Fig. 4: In silico analysis.
Fig. 5: Mislocalization of mutant GJA8s expressed in HLECs.

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Data availability

The genetic variants of GJA8 identified in this study have been submitted to ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/). The accession numbers for G46E and D51N are SCV003920679 and SCV004011733, respectively. All other data are available within the article or upon reasonable request.

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Acknowledgements

The authors thank all the participants in this study.

Funding

The National Natural Science Foundation of China (nos. 81770935 (HZ), 82371059 (HZ), 81800830 (SD)), the grant from the Department of Science and Technology of Sichuan Province, China (nos. 2023JDZH0002 (HZ), 2022JDTD0024 (BG)), the Chengdu Science and Technology Bureau (no. 2022-YF05-01984-SN (HZ)), Young and Middle-aged Health Science and Technology Innovation Talent Training Project (Outstanding Young Persons) of Henan Province (no. YXKC2022025) (SD), Medical Science and Technology Project (the Key Project Jointly Built by the Province and the Ministry) of Henan Province (no. SBGJ202102167, (SD)), and the Key Research and Development and Promotion Project (Science and Technology) program of Henan Province (no. 192102310077 (SD)).

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Author notes

  1. These authors contributed equally: Shuqian Dong, Tongdan Zou.

Authors and Affiliations

  1. Department of Ophthalmology, The First Affiliated Hospital of Zhengzhou University, Henan Provincial Ophthalmic Hospital, Zhengzhou, China

    Shuqian Dong, Fangyuan Zhen, Yongwei Zhou, Jiahui Wu & Qiuming Li

  2. The Key Laboratory for Human Disease Gene Study of Sichuan Province and Department of Laboratory Medicine, Sichuan Provincial People’s Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, China

    Tongdan Zou, Ting Wang, Bo Gong & Houbin Zhang

  3. Department of Ophthalmology, University of Occupational and Environmental Health, Kitakyushu, Japan

    Tatsuo Nagata, Itsuka Matsushita & Hiroyuki Kondo

  4. Research Unit for Blindness Prevention of Chinese Academy of Medical Sciences (2019RU026), Sichuan Academy of Medical Sciences & Sichuan Provincial People’s Hospital, Chengdu, Sichuan, China

    Houbin Zhang

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Contributions

SD, WZ, and QL recruited the Chinese participants. TZ, FZ, TW, and JW performed sequencing, vector construction, and cell culture, and analyzed the data. TN, IM, HK recruited the Japanese participants, performed the experiments and analyzed the data. SD, GB, QL, and HZ designed the experiments, and analyzed the data. QL and HZ supervised the project. TZ and HZ wrote the manuscript.

Corresponding authors

Correspondence to Qiuming Li or Houbin Zhang.

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Ethical

This study complied with the requirements of the Declaration of Helsinki, and was approved by ethics committees of all participating institutions, including the First Affiliated Hospital of Zhengzhou University, China; Sichuan Provincial People’s Hospital, China; and the University of Occupational and Environmental Health, Japan. Written informed consent for publication of details and images was obtained from all the participants or their guardians.

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Dong, S., Zou, T., Zhen, F. et al. Association of variants in GJA8 with familial acorea-microphthalmia-cataract syndrome. Eur J Hum Genet 32, 413–420 (2024). https://doi.org/10.1038/s41431-023-01503-9

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