Transcriptional regulation of PRPF31 gene expression by MSR1 repeat elements causes incomplete penetrance in retinitis pigmentosa

Scientific Reports
Anna M RoseShomi S Bhattacharya

Abstract

PRPF31-associated retinitis pigmentosa presents a fascinating enigma: some mutation carriers are blind, while others are asymptomatic. We identify the major molecular cause of this incomplete penetrance through three cardinal features: (1) there is population variation in the number (3 or 4) of a minisatellite repeat element (MSR1) adjacent to the PRPF31 core promoter; (2) in vitro, 3-copies of the MSR1 element can repress gene transcription by 50 to 115-fold; (3) the higher-expressing 4-copy allele is not observed among symptomatic PRPF31 mutation carriers and correlates with the rate of asymptomatic carriers in different populations. Thus, a linked transcriptional modifier decreases PRPF31 gene expression that leads to haploinsufficiency. This result, taken with other identified risk alleles, allows precise genetic counseling for the first time. We also demonstrate that across the human genome, the presence of MSR1 repeats in the promoters or first introns of genes is associated with greater population variability in gene expression indicating that copy number variation of MSR1s is a generic controller of gene expression and promises to provide new insights into our understanding of gene expression regulation.

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Citations

Jun 16, 2016·RNA Biology·Šárka Růžičková, David Staněk
Oct 14, 2016·Genetics in Medicine : Official Journal of the American College of Medical Genetics·Kinga M BujakowskaEric A Pierce
May 17, 2017·Human Molecular Genetics·G Jane FarrarPete Humphries
May 28, 2019·International Journal of Molecular Sciences·Michalitsa DiakatouVasiliki Kalatzis
Jun 24, 2017·Genetics·Yuelong GuoDahlia M Nielsen
Aug 14, 2018·Documenta Ophthalmologica. Advances in Ophthalmology·Sofia BhatiaVanita Vanita
Feb 23, 2020·Frontiers in Neuroscience·Frances TheunissenPatrick Anthony Akkari
Jan 2, 2020·Molecular Medicine·Lourdes Valdés-SánchezFrancisco J Díaz-Corrales
Mar 16, 2017·Cold Spring Harbor Perspectives in Biology·Kinga M BujakowskaEric A Pierce
Mar 7, 2021·International Journal of Molecular Sciences·Izarbe Aísa-MarínGemma Marfany
Feb 10, 2020·The Journal of Molecular Diagnostics : JMD·Ana Rodríguez-MuñozJosé M Millán
Apr 13, 2021·Frontiers in Aging Neuroscience·Frances TheunissenP Anthony Akkari
Jun 3, 2021·International Journal of Molecular Sciences·Adrian DockeryG Jane Farrar
Aug 17, 2021·Frontiers in Cell and Developmental Biology·Chunbo YangMajlinda Lako

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Methods Mentioned

BETA
PCR
transfection
transfections

Software Mentioned

GeneMarker
EMBOSS Newcpgreport
RepeatMasker browser

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