SNRNP200 Mutations Cause Autosomal Dominant Retinitis Pigmentosa

Tao Zhang, Jingshan Bai, Xinyi Zhang, Xiaowei Zheng, Nan Lu, Zhongyin Liang, Ling Lin, Yongsong Chen | Frontiers in Medicine


The small nuclear ribonucleoprotein 200 kDa (SNRNP200) gene plays a key role in the maturation of pre-message RNA (pre-mRNA) splicing with the indication for the etiology of retinitis pigmentosa (RP). Gene recognition can facilitate the diagnosis of these patients for better clinical management, treatment and counseling. This study aimed to outline the causative mutation in a Chinese family and the pathogenic mechanism of this SNRNP200 mutation in RP. Eighteen individuals from the affected family underwent a complete ophthalmic examination. Whole exome sequencing (WES) was conducted to identify the pathogenic variant in the proband, which was then confirmed by Sanger sequencing. Expression of the SNRNP200 transcript in zebrafish was identified via whole mount in situ hybridization. Morpholino oligonucleotide (MO) and SNRNP200 wild and mutant mRNA were injected into zebrafish embryos followed by analyses of the systemic changes and retinal phenotypes using immunofluorescence. Heterozygous SNRNP200c.C6088T (p.Arg2030Cys) mutation was ascertained in two members of this family: the proband and his father (II-2). Overexpression of SNRNP200Arg2030Cys, but not SNRNP200WT caused systemic deformities in the wild-type zebrafish embryos with the retina primarily injured, and significantly increased death rates in the morphant embryos, in which the orthologous zebrafish SNRNP200 gene was blocked. In conclusion, this study reports a novel heterozygous SNRNP200c.C6088T mutation, which is evidenced to cause RP via a dominant-negative effect.


Retinitis pigmentosa (RP) is reported as the most regular form of inherited degenerative retinal dystrophy, with a prevalence ranging between 1/3,500 to 1/5,000 among different countries worldwide (1, 2). Nyctalopia is one of the earliest and most common symptoms of RP, followed by subsequent constricted visual fields (VFs), and eventual loss of central vision caused by the degeneration of photoreceptor and retinal pigment epithelium (RPE) (3, 4). The fundus in RP is characterized by peripheral bone-spicule pigmentary deposits, attenuation of the artery, and waxy pallor of the optic nerve head. Outer nuclear layer attenuation and the loss of outer/inner segments of RPE in the macular area of the retina are the typical characteristics. The inheritance of RP could be in three modes, autosomal dominant RP (adRP), autosomal recessive RP, and X-linked RP. Thus far, 307 genes and gene loci have been shown to be involved in retina degeneration [Retnet database; reviewed in Daiger et al. (5)]. The majority of these genes are specifically expressed in the retina. Interestingly, 6 of 22 adRP-related genes code for universally expressed pre-mRNA splicing proteins that are essential splicing factors, called the small nuclear ribonucleoprotein particles (snRNPs). These genes include PRPF6 (MIM 613979) (6), PRPF31(MIM 606419) (7), PRPF8 (MIM 607300) (8), PRPF3 (MIM 607301) (9), PIM1-associated protein [RP9 (MIM 607331)] (10), and small nuclear ribonucleoprotein 200 kDa (SNRNP200) (11, 12).

For most eukaryotic genes, the primarily transcribed RNA from the gene's DNA must be edited through a process called splicing before it becomes mature, and only then can it guide the synthesis of proteins. During the process of primary RNA editing, the sequence of the introns will be removed and the sequence of the exons will be connected together, through the actions of the spliceosome, primarily comprising U1, U2, U4/U6, and U5 snRNPs. The complex of U4/U6–U5 tri-snRNP is essential for installing and the catalytic process of the spliceosome structural rearrangements. Thus, any defect in the complex could possibly contribute to the pathogenesis of RP (13).

SNRNP200 encodes hBrr2, which is one of the U5 snRNP-specific proteins (NP_054733.2) (14), containing 2,136 amino acids (15) and catalyzing the U4/U6 unwinding (16). It has been reported in the literature that the mutation of SNRNP200 can compromise the U4/U6 unwinding (11) and when blocked, could cause the demorphogenesis of rod photoreceptors in a zebrafish model (17). However, the exact pathogenic mechanism of the SNRNP200 mutations has never been demonstrated.

Herein, we report one naturally occurring heterozygous mutation in SNRNP200, c.C6088T (p.Arg2030Cys), which associates with adRP in a Chinese family and investigate the pathogenic mechanism of this SNRNP200 mutation.

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