Transcriptional Expression ofCis-Acting and Trans-Acting Splicing Mutations Cause Autosomal Dominant Retinitis Pigmentosa

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Two types of mutations may lead to deficient pre-mRNA splicing:cis-acting mutations that inactivate a constitutive or alternative splice site within the pre-mRNA, andtrans-acting mutations that affect the function of a basal factor of the splicing machinery. Autosomal dominant retinitis pigmentosa (adRP) is caused by mutations in at least 12 genes, with mutations in rhodopsin being the most prevalent. Twocis-acting mutations, g.3811A>G and g.5167G>T at the splice site in the rhodopsin gene (RHO; GenBank U49742.1) are linked to adRP in a Spanish population; while acis-acting mutation, g.4335G>T, has been linked to recessive RP (arRP). Transcriptional expression analysis showed that thecis-acting splicing mutations linked to adRP promoted alternative splice sites, while the arRP linked mutation results in exclusion of exon 4.Trans-acting splicing mutations associated with adRP have also been found, and mutations in the pre-mRNA splicing factorsPRPF3,PRPF8,PRPF31, andRP9are associated with adRP in several populations. This report describes a new mutation inPRPF3in a Spanish adRP family. We also investigated the transcriptional patterns in Epstein-Barr virus (EBV)-transformed lymphoblastoid cells from patients carrying a mutation inPRPF8. Despite the role ofPRPF8in the minor U12 splicing processes, microarray analysis revealed that mutations inPRPF8not only did not result in significant differences in splicing efficiency of rhodopsin, but no apparent changes in expression of U12-type intron genes and splicing processes was observed. Microarray analysis revealed a panel of differentially expressed genes mapped to the RP loci, and future work will determine their role in RP. Hum Mutat 29(6), 869-878, 2008.

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