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.
CriswickVGSchepensCL. Familial exudative vitreoretinopathy. Am J Ophthalmol1969; 68: 578–594.
2.
van NouhuysCE. Signs, complications, and platelet aggregation in familial exudative vitreoretinopathy. Am J Ophthalmol1991; 111: 34–41. 1991/01/15.
3.
NikopoulosKGilissenCHoischenA, et al. Next-generation sequencing of a 40 Mb linkage interval reveals TSPAN12 mutations in patients with familial exudative vitreoretinopathy. Am J Hum Genet2010; 86: 240–247. 2010/02/18.
4.
ShastryBSHejtmancikJFTreseMT. Identification of novel missense mutations in the norrie disease gene associated with one X-linked and four sporadic cases of familial exudative vitreoretinopathy. Hum Mutat1997; 9: 396–401. 1997/01/01.
5.
ShastryBSTreseMT. Familial exudative vitreoretinopathy: further evidence for genetic heterogeneity. Am J Med Genet1997; 69: 217–218. 1997/03/17.
6.
NishimuraMYamanaTSuginoM, et al.Falciform retinal fold as sign of familial exudative vitreoretinopathy. Jpn J Ophthalmol1983; 27: 40–53. 1983/01/01.
7.
RanchodTMHoLYDrenserKA, et al. Clinical presentation of familial exudative vitreoretinopathy. Ophthalmology2011; 118: 2070–2075. 2011/08/27.
8.
YeXWangYCahillH, et al.Norrin, frizzled-4, and Lrp5 signaling in endothelial cells controls a genetic program for retinal vascularization. Cell2009; 139: 285–298.
9.
ZhuXYangMZhaoP, et al. Catenin alpha 1 mutations cause familial exudative vitreoretinopathy by overactivating norrin/beta-catenin signaling. J Clin Invest 2021; 131: e139869. 2021/03/15.
10.
ZhangSLiXLiuW, et al. Whole-Exome sequencing identified DLG1 as a candidate gene for familial exudative vitreoretinopathy. Genet Test Mol Biomarkers2021; 25: 309–316. 2021/05/05.
11.
ParkHYamamotoHMohnL, et al. Integrin-linked kinase controls retinal angiogenesis and is linked to Wnt signaling and exudative vitreoretinopathy. Nat Commun2019; 10: 5243. 2019/11/22..
12.
YeXWangYNathansJ. The norrin/Frizzled4 signaling pathway in retinal vascular development and disease. Trends Mol Med2010; 16: 417–425. 2010/08/07.
13.
YangMLiSLiuW, et al. The ER membrane protein complex subunit Emc3 controls angiogenesis via the FZD4/WNT signaling axis. Sci China Life Sci 2021; 64: 1868–1883. 2021/11/01.
14.
ChenCYangMHuangL, et al. Whole-Exome sequencing reveals novel TSPAN12 variants in autosomal dominant familial exudative vitreoretinopathy. Genet Test Mol Biomarkers2021; 25: 399–404. 2021/06/03.
15.
CleversH. Eyeing up new Wnt pathway players. Cell2009; 139: 227–229. 2009/10/20.
16.
DrenserKAFeckoADaileyW, et al. A characteristic phenotypic retinal appearance in norrie disease. Retina2007; 27: 243–246. 2007/02/10..
17.
CollinRWNikopoulosKDonaM, et al. ZNF408 Is mutated in familial exudative vitreoretinopathy and is crucial for the development of zebrafish retinal vasculature. Proc Natl Acad Sci USA2013; 110: 9856–9861. 2013/05/30.
18.
XiaFLyuJFeiP, et al.Diagnosis of complicated FEVR preoperatively and intra-/post-operatively: characteristics and risk factors for diagnostic timing. BMC Ophthalmol2019; 19: 26.
19.
TauqeerZYonekawaY. Familial exudative vitreoretinopathy: pathophysiology, Diagnosis, and Management. Asia-Pacific journal of ophthalmology2018; 7: 176–182.
20.
RichardsSAzizNBaleS, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American college of medical genetics and genomics and the association for molecular pathology. Genet Med2015; 17: 405–424. 2015/03/06.
21.
MeindlALorenzBAchatzH, et al. Missense mutations in the NDP gene in patients with a less severe course of norrie disease. Hum Mol Genet1995; 4: 489–490. 1995/03/01.
22.
ChenZYBattinelliEMHendriksRW, et al. Norrie disease gene: characterization of deletions and possible function. Genomics1993; 16: 533–535. 1993/05/01.
23.
RobitailleJMWallaceKZhengB, et al. Phenotypic overlap of familial exudative vitreoretinopathy (FEVR) with persistent fetal vasculature (PFV) caused by FZD4 mutations in two distinct pedigrees. Ophthalmic Genet2009; 30: 23–30. 2009/01/28.
24.
RaoFQCaiXBChengFF, et al. Mutations in LRP5,FZD4, TSPAN12, NDP, ZNF408, or KIF11 genes account for 38.7% of Chinese patients With familial exudative vitreoretinopathy. Invest Ophthalmol Vis Sci2017; 58: 2623–2629. 2017/05/12.
25.
XuQWangYDabdoubA, et al.Vascular development in the retina and inner ear: control by norrin and frizzled-4, a high-affinity ligand-receptor pair. Cell2004; 116: 883–895.
26.
LuhmannUFLinJAcarN, et al.Role of the norrie disease pseudoglioma gene in sprouting angiogenesis during development of the retinal vasculature. Invest Ophthalmol Visual Sci2005; 46: 3372–3382.
27.
XiaCHLiuHCheungD, et al. A model for familial exudative vitreoretinopathy caused by LPR5 mutations. Hum Mol Genet2008; 17: 1605–1612. 2008/02/12.
28.
JungeHJYangSBurtonJB, et al.TSPAN12 Regulates retinal vascular development by promoting norrin- but not Wnt-induced FZD4/beta-catenin signaling. Cell2009; 139: 299–311.
29.
MeitingerTMeindlABorkP, et al. Molecular modelling of the norrie disease protein predicts a cystine knot growth factor tertiary structure. Nat Genet1993; 5: 376–380. 1993/12/01.
30.
KeJHarikumarKGEriceC, et al.Structure and function of norrin in assembly and activation of a frizzled 4-Lrp5/6 complex. Genes Dev2013; 27: 2305–2319.
31.
ChangTHHsiehFLZebischM, et al.Structure and functional properties of norrin mimic Wnt for signalling with Frizzled4, Lrp5/6, and proteoglycan. eLife 2015; 4: e06554. 2015/07/09.
32.
XiaoHTongYZhuY, et al. Familial exudative vitreoretinopathy-related disease-causing genes and norrin/beta-catenin signal pathway: structure, function, and mutation spectrums. J Ophthalmol2019; 2019: 5782536. 2019/12/13.
33.
SmallwoodPMWilliamsJXuQ, et al. Mutational analysis of norrin-Frizzled4 recognition. J Biol Chem2007; 282: 4057–4068. 2006/12/13.
34.
RathiSJalaliSMusadaGR, et al.Mutation spectrum of NDP, FZD4 and TSPAN12 genes in Indian patients with retinopathy of prematurity. Br J Ophthalmol2018; 102: 276–281.
35.
RoyerGHaneinSRaclinV, et al.NDP Gene mutations in 14 French families with norrie disease. Hum Mutat2003; 22: 99.
36.
NikopoulosKVenselaarHCollinRW, et al.Overview of the mutation spectrum in familial exudative vitreoretinopathy and norrie disease with identification of 21 novel variants in FZD4, LRP5, and NDP. Hum Mutat2010; 31: 656–666.
37.
BlackGCPerveenRBonshekR, et al.Coats’ disease of the retina (unilateral retinal telangiectasis) caused by somatic mutation in the NDP gene: a role for norrin in retinal angiogenesis. Hum Mol Genet1999; 8: 2031–2035.
38.
HanSSunJYangL, et al.Role of NDP- and FZD4-related novel mutations identified in patients with FEVR in norrin/beta-catenin signaling pathway. BioMed Res Int2020; 2020: 7681926.
39.
TangMSunLHuA, et al. Mutation Spectrum of the LRP5, NDP, and TSPAN12 genes in Chinese patients With familial exudative vitreoretinopathy. Invest Ophthalmol Vis Sci2017; 58: 5949–5957. 2017/11/29.
40.
ShastryBSHiraokaMTreseDC, et al.Norrie disease and exudative vitreoretinopathy in families with affected female carriers. Eur J Ophthalmol1999; 9: 238–242.
41.
ChenZYBattinelliEMWoodruffG, et al. Characterization of a mutation within the NDP gene in a family with a manifesting female carrier. Hum Mol Genet1993; 2: 1727–1729. 1993/10/01.
42.
SimsKBIrvineARGoodWV. Norrie disease in a family with a manifesting female carrier. Arch Ophthalmol1997; 115: 517–519. 1997/04/01.
