Dominant mutations in the mRNA splicing factor gene PRPF31 (RP11) cause retinitis pigmentosa with reduced penetrance. We studied the expression of RP11 in lymphoblast cell lines from 10 patients, including three who were clinically asymptomatic, with six distinct RP11 mutations. Five of the six mutations were characterized and all five created premature nonsense codons or eliminated the normal initiation codon. Semiquantitative RT-PCR indicated that an average of only 17% of the RP11 mRNA was derived from the mutant allele, likely because the mutant mRNA transcripts were degraded by nonsense-mediated decay. Gene expression levels were measured by Affymetrix and CodeLink microarrays and, for RP11 transcripts, also by real-time PCR. Combined wild-type-plus-mutant RP11 mRNA expression from symptomatic patients was 52 to 77% of that in controls (p≤0.0005). Clinically asymptomatic carriers had levels of RP11 mRNA similar to controls and 29–42% higher than in clinically affected patients (0.0001<p<0.05, varying according to measurement technique). Expression levels of seven housekeeping genes (4–15 exons each) and 11 single-exon histone genes showed no substantial differences between affected patients with RP11 mutations and controls. Our results indicate that penetrance of dominant RP11 mutations correlates with the expression level of the remaining wild-type RP11 allele. Because RP11 mutations are apparently null alleles and because nonpenetrance correlates with high wild-type allele expression, the phenotypic effect of RP11 mutations is likely due to haploinsufficiency. The similar mRNA expression levels from genes with and without introns suggest that there is no generalized RNA splicing abnormality in RP11 patients. Hum Mutat 27(7), 644–653, 2006. Published 2006 Wiley-Liss, Inc.
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