2. Academic Validation
  3. A novel frameshift variant in the TSPAN12 gene causes autosomal dominant FEVR

A novel frameshift variant in the TSPAN12 gene causes autosomal dominant FEVR

  • Mol Genet Genomic Med. 2022 Jun;10(6):e1949. doi: 10.1002/mgg3.1949.
Li Peng 1 2,  Erkuan Dai 3,  Haodong Xiao 3,  Rulian Zhao 1,  Yunqi He 1 2,  Shujin Li 1 2 4,  Mu Yang 1 2 4,  Zhenglin Yang 1 2 4,  Peiquan Zhao 3
Affiliations

Affiliations

  • 1 Sichuan Provincial Key Laboratory for Human Disease Gene Study and Department of Laboratory Medicine, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China.
  • 2 Natural Products Research Center, Institute of Chengdu Biology, Sichuan Translational Medicine Hospital, Chinese Academy of Sciences, Chengdu, China.
  • 3 Department of Ophthalmology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 4 Research Unit for Blindness Prevention of Chinese Academy of Medical Sciences (2019RU026), Sichuan Academy of Medical Sciences, Chengdu, China.
PMID: 35417085 DOI: 10.1002/mgg3.1949
Abstract

Background: Familial exudative vitreoretinopathy (FEVR) is an inherited blinding eye disease with abnormal retinal vascular development. We aim to broaden the variant spectrum of FEVR and provide a basis for molecular diagnosis and genetic consultation.

Methods: We recruited five FEVR patients from one large Chinese family. Whole-exome sequencing (WES) and Sanger sequencing were applied to sequence, analyze, and verify variants on genomic DNA samples. Immunocytochemistry, western blot, qPCR, and luciferase assay were performed to test the influence of the variant on the protein expression and activity of the Norrin/β-catenin pathway.

Results: We identified a novel heterozygous frameshift variant c.533dupC (p.D179Rfs*6) in Tetraspanin 12 (TSPAN12) gene that is related to FEVR. This variant caused degradation of the entire TSPAN12 protein, which failed to activate Norrin/β-catenin signaling, possibly causing FEVR.

Conclusion: Our study revealed a novel frameshift variant D179Rfs*6 in TSPAN12 that is inherited in an autosomal dominant manner. We found that D179Rfs*6 caused a failure to activate Norrin/β-catenin signaling. This finding broadens the variant spectrum of TSPAN12 and provides invaluable information for the molecular diagnosis of FEVR.

Keywords

TSPAN12; FEVR; Norrin/β-catenin pathway; frameshift variant.

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