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A Combined in silico, in vitro and clinical approach to characterize novel pathogenic missense variants in PRPF31 in retinitis pigmentosa

A Combined in silico, in vitro and clinical approach to characterize novel pathogenic missense variants in PRPF31 in retinitis pigmentosa
A Combined in silico, in vitro and clinical approach to characterize novel pathogenic missense variants in PRPF31 in retinitis pigmentosa
At least six different proteins of the spliceosome, including PRPF3, PRPF4, PRPF6, PRPF8, PRPF31, and SNRNP200, are mutated in autosomal dominant retinitis pigmentosa (adRP). These proteins have recently been shown to localize to the base of the connecting cilium of the retinal photoreceptor cells, elucidating this form of RP as a retinal ciliopathy. In the case of loss-of-function variants in these genes, pathogenicity can easily be ascribed. In the case of missense variants, this is more challenging. Furthermore, the exact molecular mechanism of disease in this form of RP remains poorly understood. In this paper we take advantage of the recently published cryo EM-resolved structure of the entire human spliceosome, to predict the effect of a novel missense variant in one component of the spliceosome; PRPF31, found in a patient attending the genetics eye clinic at Bristol Eye Hospital. Monoallelic variants in PRPF31 are a common cause of autosomal dominant retinitis pigmentosa (adRP) with incomplete penetrance. We use in vitro studies to confirm pathogenicity of this novel variant PRPF31 c.341T > A, p.Ile114Asn. This work demonstrates how in silico modeling of structural effects of missense variants on cryo-EM resolved protein complexes can contribute to predicting pathogenicity of novel variants, in combination with in vitro and clinical studies. It is currently a considerable challenge to assign pathogenic status to missense variants in these proteins.
1664-8021
Wheway, Gabrielle
2e547e5d-b921-4243-a071-2208fd4cc090
Nazlamova, Liliya
0cc21013-aeeb-4eef-af56-31f6fa0766fd
Meshad, Nervine
937c5253-ba2f-4d5d-8ff8-8b04d87f5b69
Hunt, Samantha
b6597583-77dc-4671-b473-c96fb3a5b484
Jackson, Nicola
83dcea4d-2fe7-406c-a134-1066c1e71efc
Churchill, Amanda
d00d3f84-5359-46d5-8290-ff9887859038
Wheway, Gabrielle
2e547e5d-b921-4243-a071-2208fd4cc090
Nazlamova, Liliya
0cc21013-aeeb-4eef-af56-31f6fa0766fd
Meshad, Nervine
937c5253-ba2f-4d5d-8ff8-8b04d87f5b69
Hunt, Samantha
b6597583-77dc-4671-b473-c96fb3a5b484
Jackson, Nicola
83dcea4d-2fe7-406c-a134-1066c1e71efc
Churchill, Amanda
d00d3f84-5359-46d5-8290-ff9887859038

Wheway, Gabrielle, Nazlamova, Liliya, Meshad, Nervine, Hunt, Samantha, Jackson, Nicola and Churchill, Amanda (2019) A Combined in silico, in vitro and clinical approach to characterize novel pathogenic missense variants in PRPF31 in retinitis pigmentosa. Frontiers in Genetics, 10. (doi:10.3389/fgene.2019.00248).

Record type: Article

Abstract

At least six different proteins of the spliceosome, including PRPF3, PRPF4, PRPF6, PRPF8, PRPF31, and SNRNP200, are mutated in autosomal dominant retinitis pigmentosa (adRP). These proteins have recently been shown to localize to the base of the connecting cilium of the retinal photoreceptor cells, elucidating this form of RP as a retinal ciliopathy. In the case of loss-of-function variants in these genes, pathogenicity can easily be ascribed. In the case of missense variants, this is more challenging. Furthermore, the exact molecular mechanism of disease in this form of RP remains poorly understood. In this paper we take advantage of the recently published cryo EM-resolved structure of the entire human spliceosome, to predict the effect of a novel missense variant in one component of the spliceosome; PRPF31, found in a patient attending the genetics eye clinic at Bristol Eye Hospital. Monoallelic variants in PRPF31 are a common cause of autosomal dominant retinitis pigmentosa (adRP) with incomplete penetrance. We use in vitro studies to confirm pathogenicity of this novel variant PRPF31 c.341T > A, p.Ile114Asn. This work demonstrates how in silico modeling of structural effects of missense variants on cryo-EM resolved protein complexes can contribute to predicting pathogenicity of novel variants, in combination with in vitro and clinical studies. It is currently a considerable challenge to assign pathogenic status to missense variants in these proteins.

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fgene-10-00248 - Version of Record
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Accepted/In Press date: 5 March 2019
e-pub ahead of print date: 22 March 2019

Identifiers

Local EPrints ID: 429672
URI: https://eprints.soton.ac.uk/id/eprint/429672
ISSN: 1664-8021
PURE UUID: e06aefbc-5ed1-4949-ba37-ba5a784b4556
ORCID for Gabrielle Wheway: ORCID iD orcid.org/0000-0002-0494-0783

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Date deposited: 03 Apr 2019 16:30
Last modified: 20 Jul 2019 00:21

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