Pathogenesis and clinical features of congenital stationary night blindness in case of c.283delC NYX gene mutation

The complete form of X-linked congenital stationary night blindness (CSNB) is a rare genetic disease caused by a mutation in the NYX gene. CSNB is associated with the mutations taking place in 17 genes, whilst its CSNB1A form is caused by the mutations in the NYX gene, which were characterized earlier, although nothing had been reported so far about the Russian founder principle. The paper analyzes the pathogenetic mechanisms in a family with diagnosed CSNB1A and a new genetically confirmed mutation in the NYX gene in four members of one Russian family. Two brothers of the four siblings (two boys, two girls) with congenital stationary night blindness, diagnosed in early childhood, and high myopia underwent a standard ophthalmic examination, supplemented with OCT, electroretinography and color blind test with tables by Rabkin and Farnsworth test, whereupon they were sent to molecular genetics confirmation of the diagnosis by whole exome sequencing with subsequent Sanger sequencing confirmation of the detected mutation in the proband and proband’s relatives. In members of the family with clinical features of CSNB1A the reading frame shift mutation was genetically confirmed in the NYX gene (c.283delC, p.His95fs, NM_022567.2). This mutation is inherited in X-linked form. This is the first report of a case with a novel and probable founder mutation from Russia associated with CSNB1A. Since the mRNA of a NYX gene consists of only 2696 base pairs, a gene replacement therapy, or CRISPR-based gene editing, or a similar approach may be envisaged for the correction of frameshift in His95fs position.

CSNB1A, NYX, congenital stationary night blindness, gene therapy, leucine-rich domain

1. Zeitz C., Robson A.G., Audo I. Congenital stationary night blindness: an analysis and update of genotype-phenotype correlations and pathogenic mechanisms. Prog. Retin. Eye Res. 2015; 45: 58–110. doi: 10.1016/j.preteyeres.2014.09.001

2. Boycott K.M., Sauvé Y., MacDonald I.M. X-Linked Congenital Stationary Night Blindness. In: Adam M.P., Ardinger H.H., Pagon R.A., et al. (Eds). GeneReviews® [Internet]. 2012; Seattle (WA): University of Washington, Seattle.

3. Bech-Hansen N.T., Naylor M.J., Maybaum T.A., et al. Mutations in NYX, encoding the leucine-rich proteoglycan nyctalopin, cause X-linked complete congenital stationary night blindness. Nat. Genet. 2000; 26 (3): 319–23. doi: 10.1038/81619

4. Yip S.P., Li C.C., Yiu W.C., et al. A novel missense mutation in the NYX gene associated with high myopia. Ophthalmic Physiol Opt. 2013; 33 (3): 346–53. doi: 10.1111/opo.12036

5. Pearring J.N., Bojang P. Jr., Shen Y., et al. A role for nyctalopin, a small leucine-rich repeat protein, in localizing the TRP melastatin 1 channel to retinal depolarizing bipolar cell dendrites. J Neurosci. 2011; 31 (27): 10060–66. doi: 10.1523/JNEUROSCI.1014-11.2011

6. Khan N.W., Kondo M., Hiriyanna K.T., et al. Primate retinal signalling pathways: suppressing ON-pathway activity in monkey with glutamate analogues mimics human CSNB1-NYX genetic night blindness. J. Neurophysiol. 2005; 93 (1): 481–92. doi: 10.1152/jn.00365.2004

7. Gregg R.G., Kamermans M., Klooster J., et al. Nyctalopin expression in retinal bipolar cells restores visual function in a mouse model of complete X-linked congenital stationary night blindness. J. Neurophysiol. 2007; 98 (5): 3023–33. doi: 10.1152/jn.00608.2007

8. McKenna A., Hanna M., Banks E., et al. The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. Genome Res. 2010; 20 (9): 1297–303. doi: 10.1101/gr.107524.110

9. Engelhardt K.R., Xu Y., Grainger A., et al. Identification of heterozygous single- and multi-exon deletions in IL7R by whole exome sequencing. J. Clin. Immunol. 2017; 37 (1): 42–50. doi: 10.1007/s10875-016-0343-9

10. Ivanova M.E., Trubilin V.N., Atarshchikov D.S., et al. Genetic screening of Russian Usher syndrome patients toward selection for gene therapy. Ophthalmic. Genet. 2018; 39 (6): 706–13. doi: 10.1080/13816810.2018.1532527

11. Löytynoja A., Goldman N. webPRANK: a phylogeny-aware multiple sequence aligner with interactive alignment browser. BMC Bioinformatics. 2010; 11: 579. doi: 10.1186/1471-2105-11-579

12. Marchler-Bauer A., Bo Y., Han L., et al. CDD/SPARCLE: functional classification of proteins via subfamily domain architectures. Nucleic Acids Res. 2017; 45 (D1): D200-D203. doi: 10.1093/nar/gkw1129

13. Kelley L.A., Mezulis S., Yates C.M., et al. The Phyre2 web portal for protein modelling, prediction and analysis. Nat. Protoc. 2015; 10 (6): 845–58. doi: 10.1038/nprot.2015.053

14. Malaichamy S., Sen P., Sachidanandam R., et al. Molecular profiling of complete congenital stationary night blindness: a pilot study on an Indian cohort. Mol. Vis. 2014; 20: 341–51.

15. Leroy B.P., Budde B.S., Wittmer M., et al. A common NYX mutation in Flemish patients with X linked CSNB. Br. J. Ophthalmol. 2009; 93 (5): 692–6. doi: 10.1136/bjo.2008.143727

16. Dai S., Ying M., Wang K., et al. Two novel NYX gene mutations in the chinese families with X-linked congenital stationary night blindness. Sci Rep. 2015; 5: 12679. doi: 10.1038/ srep12679

17. Scalabrino M.L., Boye S.L., Fransen K.M., et al. Intravitreal delivery of a novel AAV vector targets ON bipolar cells and restores visual function in a mouse model of complete congenital stationary night blindness. Hum. Mol. Genet. 2015; 24 (21): 6229–39. doi: 10.1093/ hmg/ddv341

18. Xu C.L., Cho G.Y., Sengillo J.D., et al. Translation of CRISPR genome surgery to the bedside for retinal diseases. Front. Cell Dev. Biol. 2018;6:46. doi: 10.3389/fcell.2018.00046