2. Academic Validation
  3. Characterization of a novel heterozygous frameshift variant in NDP gene that causes familial exudative vitreoretinopathy in female patients

Characterization of a novel heterozygous frameshift variant in NDP gene that causes familial exudative vitreoretinopathy in female patients

  • Mol Genet Genomics. 2024 Mar 13;299(1):32. doi: 10.1007/s00438-024-02128-3.
Mu Yang # 1 2,  Li Peng # 1 2,  Liting Lv # 1 2,  Erkuan Dai 3,  Yunqi He 1 2,  Rulian Zhao 1 2,  Shujin Li 4 5
Affiliations

Affiliations

  • 1 Sichuan Provincial Key Laboratory for Human Disease Gene Study, Department of Laboratory Medicine, Center for Medical Genetics, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, 32 The First Ring Road West 2, Chengdu, 610072, Sichuan, China.
  • 2 Research Unit of Blindness Prevention, Chinese Academy of Medical Sciences (No. 2019RU026), Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Chengdu, China.
  • 3 Department of Ophthalmology, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 4 Sichuan Provincial Key Laboratory for Human Disease Gene Study, Department of Laboratory Medicine, Center for Medical Genetics, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, 32 The First Ring Road West 2, Chengdu, 610072, Sichuan, China. lishujin91@126.com.
  • 5 Research Unit of Blindness Prevention, Chinese Academy of Medical Sciences (No. 2019RU026), Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Chengdu, China. lishujin91@126.com.
  • # Contributed equally.
PMID: 38472449 DOI: 10.1007/s00438-024-02128-3
Abstract

Familial exudative vitreoretinopathy (FEVR) is a severe inherited disease characterized by defective retinal vascular development. With genetic and clinical heterogeneity, FEVR can be inherited in different patterns and characterized by phenotypes ranging from moderate visual defects to complete vision loss. This study was conducted to unravel the genetic and functional etiology of a 4-month-old female FEVR patient. Targeted gene panel and Sanger Sequencing were utilized for genetic evaluation. Luciferase assays, western blot, quantitive Real-Time PCR, and immunocytochemistry were performed to verify the functional defects in the identified candidate variant. Here, we report a 4-month-old girl with bilateral retinal folds and peripheral avascularization, and identified a novel frameshift heterozygous variant c.37dup (p.Leu13ProfsTer13) in NDP. In vitro experiments revealed that the Leu13ProfsTer13 variant led to a prominent decrease in protein levels instead of mRNA levels, resulting in compromised Norrin/β-catenin signaling activity. Human Androgen Receptor assay further revealed that a slight skewing of X chromosome inactivation could partially cause FEVR. Thus, the pathogenic mechanism by which heterozygous frameshift or nonsense variants in female carriers cause FEVR might largely result from a loss-of-function variant in one X chromosome allele and a slightly skewed X-inactivation. Further recruitment of more FEVR-affected females carrying NDP variants and genotype-phenotype correlation analysis can ultimately offer valuable information for the prognosis prediction of FEVR.

Keywords

NDP; FEVR; Norrin/β-catenin signaling; Skewed X chromosome inactivation.

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