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Heterozygous variants c.781G>A and c.1066dup of serine protease 56 cause familial nanophthalmos by impairing serine-type endopeptidase activity
  1. Wei Wu1,
  2. Jingjie Xu1,
  3. Houfa Yin1,
  4. Chenxi Fu1,
  5. Ke Yao1,
  6. Xiangjun Chen1,2
  1. 1Eye Center of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
  2. 2Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
  1. Correspondence to Dr Xiangjun Chen, Eye Center of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China; chenxiangjun{at}zju.edu.cn; Professor Ke Yao; xlren{at}zju.edu.cn

Abstract

Background/aims Nanophthalmos is a rare developmental, bilateral, sporadic or hereditary form of microphthalmos. In this study, the heterozygous variants c.781G>A and c.1066dup of the PRSS56 gene were identified in two patients with nanophthalmos. This study reports the clinical manifestation and the underlying pathogenic mechanism.

Methods Whole-exome sequencing was performed to identify the pathogenic genes in a Chinese family with nanophthalmos. The molecular simulation was used to predict the structures of wild-type or mutant PRSS56. The PRSS56 wild-type or mutation overexpression cellular models have been constructed accordingly. The subcellular localisation was then observed using immunofluorescence and Western-blot techniques. The Folin-Ciocalteu assay was carried out to evaluate serine-type endopeptidase activity, and a wound-healing assay was used to examine the cellular migratory ability.

Results The whole-exome sequencing revealed that heterozygous variants c.781G>A and c.1066dup of the PRSS56 gene might contribute to nanophthalmos. Both variants were not identified in the dbSNP, 1000 Genome project or ESP6500 databases. Furthermore, the variants were highly conserved and were involved in biological functions. The mutations result in destructive protein structure and impede serine-type endopeptidase activity, thereby impairing subcellular localisation and cellular migration.

Conclusion The c.781G>A and c.1066dup variants of the PRSS56 gene might negatively affect protein structures, subcellular localisation, serine-type endopeptidase activity and cellular migratory ability. Together, these changes could lead to the development of nanophthalmos. This study identifies the PRSS56 gene as a potential target for nanophthalmos diagnosis and treatment.

  • Eye (Globe)
  • Experimental – laboratory
  • Genetics

Data availability statement

All data relevant to the study are included in the article or uploaded as onlije supplemental information.

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Data availability statement

All data relevant to the study are included in the article or uploaded as onlije supplemental information.

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Footnotes

  • WW and JX are joint first authors.

  • WW and JX contributed equally.

  • Contributors XC and KY conceived, designed and supervised this work. WW and HY collected the related clinical information. WW, JX and CF performed all experiments. XC and KY analysed the data. XC and WW wrote the draft, JX, CF and KY revised it. All authors contributed to the article and approved it for publication. XC is guarantor.

  • Funding This work was supported by the National Natural Science Foundation of China (No. 31872724, No. 81900837), the Natural Science Foundation of Zhejiang Province (No. LR21H120001) and the Project from the Science Technology Department of Zhejiang Province (No. LGC19H120002).

  • Competing interests The authors declare that they have no conflicts of interest with the contents of this article.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.