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.
Highlights
Incomplete penetrance is an almost universal feature of monogenic disorders, yet the molecular basis underlying this phenomenon remains obscure in all but a few cases
We show that: (1) the human population harbors 3 or 4 copies of the MSR1 element with the 4 repeat allele conferring increased PRPF31 expression; (2) the 3 repeat allele quenches gene expression in vitro; (3) symptomatic individuals do not carry the higher-expressing 4 repeat allele; and (4) the frequency of asymptomatic individuals in different populations are correlated with the frequency of the 4 repeat allele
To further investigate the role of MSR1 in the incomplete penetrance of PRPF31-associated Autosomal dominant retinitis pigmentosa (adRP), we examined the pedigrees of all families of European and Asian (Japanese/Chinese) origin available to us for asymptomatic mutation carriers
Summary
Incomplete penetrance is an almost universal feature of monogenic disorders, yet the molecular basis underlying this phenomenon remains obscure in all but a few cases. A sentinel example of incomplete penetrance is PRPF31-associated retinitis pigmentosa, where presence of symptomatic and asymptomatic mutation carriers is a universal feature in affected families. Mutations in six ubiquitously expressed splicing factors are responsible for adRP (PRPF3, PRPF6, PRPF8, PRPF31, snRNP200 and RP9). Why mutations in such “housekeeping” genes produce a retina-specific phenotype is currently unknown. That the major rescue factor (allele) must be common and act in cis to increase PRPF31 transcription. Identifying this element is a priority since it provides insight into “natural gene therapy.”. This study demonstrates how variation in a minisatellite repeat, widely distributed across the genome, is a major determinant of disease penetrance and suggests that it is a candidate for similar phenomenon at other loci
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