A Novel Mutation in Exon 39 of PRPF8 Causes Autosomal Dominant Retinitis Pigmentosa (adRP) With Incomplete Penetrance

Abstract

Purpose: : To find the gene underlying adRP in a large English family and to determine the degree of severity in gene-carriers.

Methods: : Blood samples were obtained from ten family members. Genomic DNA was isolated and markers for know adRP genes were tested. Leukocyte RNA was extracted and PRPF8 cDNA amplified from an affected individual. Six affected patients (35-57 yrs) and 2 asymptomatic carriers (39 and 64 yrs) from that family were ascertained. All underwent full ophthalmic examination, colour vision testing, digital fundus photography. ISCEV-standard ERG, Goldman perimetry and OCT was performed on some gene-carriers.

Results: : The disease segregated with markers on chromosome 17, which included the PRPF8 locus. A novel base substitution 6445 C>T in exon 39 of PRPF8, causing a non-conservative missense mutation p.S2118F was determined and was present in all affected patients. It was not detected in 130 ethnically matched control samples. Age of onset of night blindness and severity of progression of the disease was variable between members of the same family. Visual acuities ranged from 6/9 to hand movements. One asymptomatic carrier had a normal visual acuity, normal fundus appearance and his full-field ERGs of revealed mild rod dysfunction. Other associated ocular findings included: bilateral cystoid macular edema, angle closure glaucoma and unilateral retinal telangiectasias.

Conclusions: : A novel mutation p.S2118F was detected in exon 39 of PRPF8 in a family affected by adRP. Incomplete penetrance for symptoms and signs was found in two gene-carriers. This is the first report of a mutation in PRPF8 5’ to exon 40. The clinical findings suggest that it will be worth screening PRPF8 in adRP families with incomplete penetrance particularly when PRPF31 mutation is absent.

Keywords: gene/expression • retinitis • degenerations/dystrophies