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S. J. Bowne, L. S. Sullivan, E. D. Cadena, D. H. Wheaton, J. R. Heckenlively, D. G. Birch, S. P. Daiger; A Screen for Genomic Rearrangements in Genes Known to Cause Autosomal Dominant Retinitis Pigmentosa (AdRP). Invest. Ophthalmol. Vis. Sci. 2007;48(13):2334.
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© ARVO (1962-2015); The Authors (2016-present)
To determine whether genomic rearrangements in rhodopsin, peripherin/RDS, RP1, CRX, FSCN2, or PRPF3 cause autosomal dominant retinitis pigmentosa (adRP).
Eighty-seven probands from our defined cohort of 200 adRP families, who did not have detectible mutations in the known adRP genes, were tested for genomic rearrangements using multiplex ligation-dependent probe amplification (MLPA). A subset of the known adRP genes were selected for MLPA analysis based on the likelihood that haploinsufficiency would lead to retinal degeneration. Probes were designed for all of the coding exons and promoter regions of rhodopsin, peripherin/RDS, FSCN2, and CRX as well as for mutation hotspots of RP1 and PRPF3. In addition, several adRP patients, not part of the cohort, were tested for PRPF31 deletions using previously described MLPA probes.
No genomic rearrangements were found in rhodopsin, peripherin/RDS, RP1, or PRPF3. Some probes for FSCN2 were consistently reduced in several families and the underlying cause is being investigated. One CRX probe appears to behave erratically in two families and may be indicative of a rearrangement. One novel PRPF31 deletion was identified in the additional patients tested.
We have previously shown that genomic rearrangements in the PRPF31 gene that are undetectable by sequencing cause approximately 2.5% of adRP. The likely disease mechanism of these rearrangements and other PRPF31 mutations is haploinsufficiency of the PRPF31 gene product. The additional adRP genes we have tested using MLPA have the potential to cause disease by haploinsufficiency as well, based on animal models and observed mutations. It appears that large-scale rearrangements in these genes are not an appreciable cause of adRP.
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