title: Transcriptional regulation of PRPF31 gene expression by MSR1 repeat elements causes incomplete penetrance in retinitis pigmentosa.
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.
authors.affiliation: UCL Institute of Ophthalmology, University College London, London, EC1V 9EL, UK.
authors.forename: Anna M
authors.initials: AM
authors.lastname: Rose
authors.affiliation: UCL Institute of Ophthalmology, University College London, London, EC1V 9EL, UK.
authors.forename: Amna Z
authors.initials: AZ
authors.lastname: Shah
authors.affiliation: Department of Medical Genetics, University of Lausanne, 1005 Lausanne, Switzerland.
authors.forename: Giulia
authors.initials: G
authors.lastname: Venturini
authors.affiliation: Department of Cell Therapy and Regenerative Medicine, CABIMER, 41092 Seville, Spain.
authors.forename: Abhay
authors.initials: A
authors.lastname: Krishna
authors.affiliation: Johns Hopkins University School of Medicine, Institute of Genetic Medicine, 733 N. Broadway MRB 579 Baltimore, MD 21287, USA.
authors.forename: Aravinda
authors.initials: A
authors.lastname: Chakravarti
authors.affiliation: Department of Medical Genetics, University of Lausanne, 1005 Lausanne, Switzerland.
authors.forename: Carlo
authors.initials: C
authors.lastname: Rivolta
authors.affiliation: UCL Institute of Ophthalmology, University College London, London, EC1V 9EL, UK.
authors.forename: Shomi S
authors.initials: SS
authors.lastname: Bhattacharya
mesh_terms: D000483:Alleles; D001665:Binding Sites; D017124:Conserved Sequence; D056915:DNA Copy Number Variations; D005136:Eye Proteins / Q000378:metabolism*; D015870:Gene Expression; D005786:Gene Expression Regulation; D005787:Gene Frequency; D017930:Genes, Reporter; D005828:Genetics, Population; D005838:Genotype; D006801:Humans; D059372:Nucleotide Motifs; D019683:Penetrance; D010641:Phenotype; D056510:Position-Specific Scoring Matrices; D011401:Promoter Regions, Genetic; D012091:Repetitive Sequences, Nucleic Acid; D012174:Retinitis Pigmentosa / Q000235:genetics* / Q000378:metabolism*; D051117:Scavenger Receptors, Class A / Q000235:genetics*; D014158:Transcription, Genetic
chemical_list: D005136:Eye Proteins; C495139:MSR1 protein, human; C454222:PRPF31 protein, human; D051117:Scavenger Receptors, Class A