University of Leicester
Browse
mv-v27-107.pdf (5.93 MB)

Heterozygous deletions of noncoding parts of the PRPF31 gene cause retinitis pigmentosa via reduced gene expression

Download (5.93 MB)
journal contribution
posted on 2021-11-09, 12:16 authored by Francesco Paolo Ruberto, Sara Balzano, Prasanthi Namburi, Adva Kimchi, Rosanna Pescini-Gobert, Alexey Obolensky, Eyal Banin, Tamar Ben-Yosef, Dror Sharon, Carlo Rivolta

Purpose

Heterozygous mutations in the gene PRPF31, encoding a pre-mRNA splicing factor, cause autosomal dominant retinitis pigmentosa (adRP) with reduced penetrance. At the molecular level, pathogenicity results from haploinsufficiency, as the largest majority of such mutations trigger nonsense-mediated mRNA decay or involve large deletions of coding exons. We investigated genetically two families with a history of adRP, one of whom showed incomplete penetrance.

Methods

All patients underwent thorough ophthalmological examination, including electroretinography (ERG) and Goldmann perimetry. Array-based comparative genomic hybridization (aCGH) and multiplex ligation-dependent probe amplification (MLPA) were used to map heterozygous deletions, while real-time PCR on genomic DNA and long-range PCR allowed resolving the mutations at the base-pair level. PRPF31 transcripts were quantified with real-time PCR on patient-derived lymphoblastoid cell lines.

Results

We identified two independent deletions affecting the promoter and the 5' untranslated region (UTR) of PRPF31 but leaving its coding sequence completely unaltered. Analysis of PRPF31 mRNA from lymphoblastoid cell lines from one of these families showed reduced levels of expression in patients versus controls, probably due to the heterozygous ablation of its promoter sequences.

Conclusions

In addition to reporting the identification of two novel noncoding deletions in PRPF31, this study provides strong additional evidence that mRNA-mediated haploinsufficiency is the primary cause of pathogenesis for PRPF31-linked adRP.

History

Citation

Molecular Vision 2021; 27:107-116

Author affiliation

Department of Genetics and Genome Biology

Version

  • VoR (Version of Record)

Published in

Molecular Vision

Volume

27

Pagination

107 - 116

Publisher

Molecular Vision

issn

1090-0535

eissn

1090-0535

Acceptance date

2021-03-16

Copyright date

2021

Available date

2021-11-09

Spatial coverage

United States

Language

English

Usage metrics

    University of Leicester Publications

    Categories

    Exports

    RefWorks
    BibTeX
    Ref. manager
    Endnote
    DataCite
    NLM
    DC