Whole-Exome Sequencing Reveals Novel NDP Variants in X-Linked Familial Exudative Vitreoretinopathy

Abstract

Purpose To investigate causative variants in three Chinese families affected with familial exudative vitreoretinopathy (FEVR). Methods Three unrelated Chinese families were recruited in this study. The three probands and their family members experienced a comprehensive age-appropriate eye examination and genetic analysis. Luciferase assay was performed to evaluate impacts of variants on Norrin/β-catenin signaling activity. Results Here we report two novel NDP variants associated with FEVR in three families, including c.17T>C (p.Leu6Pro) in family 1 and c.58G>A (p.Gly20Arg) in family 2 and 3. These two variants were co-segregated with the disease phenotypes within each family. In addition, both variants resulted in compromised Norrin/β-catenin signaling activity. Conclusion Our study identified two FEVR-associated pathogenic variants in NDP, which expanded the variant spectrum and provided information for the genetic diagnosis of FEVR.

A comprehensive functional analysis on the pathogenesis of novel TSPAN12 and NDP variants in familial exudative vitreoretinopathy

“…9,27 During retinal angiogenesis, Norrin acts as a ligand that binds specifically to the receptor FZD4 rather than the other FZD family members, with the involvement of co-activators LRP5/LRP6 to activate Norrin/β-catenin signaling. [28][29][30][31] TSPAN12 is an essential coreceptor of Norrin/β-catenin signaling that interacts with FZD4/ Norrin through the extracellular loop to enhance the selectivity of FZD4 for Norrin. 31,32 To date, TSPAN12 variants have been reported to cause autosomal dominant and autosomal recessive FEVR, whereas NDP variants were reported to cause X-linked FEVR and Norrie disease.…”

“…Previous genetic and functional studies have demonstrated that impairment of Norrin/β‐catenin signaling causes defects in the retinal vasculature 9,27 . During retinal angiogenesis, Norrin acts as a ligand that binds specifically to the receptor FZD4 rather than the other FZD family members, with the involvement of co‐activators LRP5/LRP6 to activate Norrin/β‐catenin signaling 28–31 . TSPAN12 is an essential co‐receptor of Norrin/β‐catenin signaling that interacts with FZD4/Norrin through the extracellular loop to enhance the selectivity of FZD4 for Norrin 31,32 .…”

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

“…The Norrin/β‐catenin pathway plays an important role in retinal vascular development (Chen et al, 1993 ; Park & Yamamoto, 2019 ; Poulter et al, 2010 ; Tucci et al, 2014 ; Yang et al, 2021 ; Zhang et al, 2021 ; Zhu et al, 2021 ). In this pathway, the extracellular ligand Norrin (encoded by NDP ) binds to a receptor complex composed of Low‐density lipoprotein receptor‐related protein‐5 (LRP5) and Frizzled‐4 (FZD4) to inhibit the degradation of β‐catenin, which activates the expression of downstream genes (Fei et al, 2015 ; Han et al, 2020 ; Panagiotou et al, 2017 ; Peng et al, 2022 ; Wang et al, 2021 ; Zhao et al, 2022 ). TSPAN12 plays a role in stabilizing ligand‐receptor complex in Norrin/β‐catenin signaling pathway (Ke et al, 2013 ; Panagiotou et al, 2017 ; Schatz & Khan, 2017 ; Xin et al, 2010 ).…”