A large deletion in the adRP gene PRPF31: evidence thathaploinsufficiency is the cause of disease

[摘要] Purpose: To report a large deletion that encompasses more than 90%of PRPF31 gene and two other neighboring genes in their entirety inan adRP pedigree that appears to show only the typical clinical featuresof retinitis pigmentosa.Methods: To identify PRPF31 mutation in a dominant RP family(ADRP2) previously linked to the RP11 locus, the 14 exons of PRPF31were screened for mutations by direct sequencing. To investigate thepossibility of a large deletion, microsatellite markers near PRPF31gene were analyzed by non-denaturing PAGE.Results: Initial screening of PRPF31 gene in the ADRP2 familydid not reveal an obvious mutation. A large deletion was howeversuspected due to lack of heterozygosity for nearly all PRPF31intragenic single nucleotide polymorphysm (SNPs). In order to estimatethe size of the deletion, SNPs and microsatellite markers spanning andflanking PRPF31 were analyzed in the entire ADRP2 family. Haplotypeanalysis with the above markers suggested a deletion of approximately 30kb that included the putative promoter region of a novel gene OSCAR,the entire genomic content of genes NDUFA3, TFPT and more than90% of PRPF31 gene. Sequence analysis of the region flanking thepotential deletion showed a high presence of Alu elementsimplicating Alu mediated recombination as the mechanism responsiblefor this event.Conclusions: This mutation provides evidence that haploinsufficiencyrather than aberrant function of mutated proteins is the cause ofdisease in these adRP patients with mutations in PRPF31 gene.

[学科分类] 生物化学/生物物理