Variability in clinical phenotypes of PRPF8-linked autosomal dominant retinitis pigmentosa correlates with differential PRPF8/SNRNP200 interactions. (2nd January 2018)

• Record Type: Journal Article
• Authors: Escher, Pascal; Passarin, Olga; Munier, Francis L.; Tran, Viet H.; Vaclavik, Veronika
• Is Part Of: Ophthalmic genetics. Volume 39:Number 1(2018)
• Page Start: 80
• Page End: 86
• Publication Date: 2018-01-02
• Subjects: BRR2 -- genotype/phenotype correlation -- PRPF8 -- retinitis pigmentosa -- SNRNP200 -- spliceosome; Eye -- Diseases -- Genetic aspects -- Periodicals; Eye Diseases -- genetics -- Periodicals; Eye Diseases -- in infancy & childhood -- Periodicals; 617.7
• DOI: 10.1080/13816810.2017.1393825
• Languages: English
• ISSNs: 1381-6810

Abstract

ABSTRACT: Purpose: To expand the genotype/phenotype correlations in patients with autosomal dominant retinitis pigmentosa (adRP) harboring PRPF8 variants. Materials and Methods: Two patients, a father and his daughter, harboring a novel p.PRPF8-Glu2331* variant, underwent ophthalmic examination at 3-year-interval, including fundus photography, fundus autofluorescence, optical coherence tomography, and ISCEV standard full field ERGs. All reported disease-causing PRPF8 variants were collected and localized in the PRPF8 and PRPF8/SNRNP200 protein structures. Results: The p.PRPF8-Glu2331* variant results in a truncated PRPF8 protein lacking the last five C-terminal amino acids and caused in the two patients a severe clinical phenotype, with the macula being affected from the second decade on. All but two adRP-linked variants are located in the last exon 43 encoding the C-terminal tail of the C-terminal PRPF8 Jab1 domain. The p.PRPF8-Ser2118Phe and -Asn2280Lys variants encoded by exons 39 and 42, respectively, are located at the basis of the C-terminal tail. Conclusions: Frame-shift mutations and nonconservative amino acid changes in PRPF8 typically cause severe clinical phenotypes. The conservative missense variant p.PRPF8-Arg2310Lys that is not altering the global charge of the C-terminal tail, and variants located at the basis of the C-terminal tail show milder clinical phenotypes, in accordance with functional data on PRPF8/SNRNP200 interactions in yeast.