Phenotypic Expression of a PRPF8 Gene Mutation in a Large African American Family

Abstract

To describe the phenotype and determine the genetic cause of autosomal dominant retinitis pigmentosa (adRP) in a large African American family. Methods: Fourteen members from 4 generations were evaluated clinically. Visual field measurements were made for most, and electroretinography, Tü binger perimetry, and optical coherence tomographic testing were done for individual family members. Genetic screening was performed on a recently introduced adRP microarray that contains approximately 400 mutations from 13 genes. Results: All of the affected members had a type 1 form of adRP, characterized by early onset of symptoms for visual impairment, marked central and peripheral vision loss, nondetectable electroretinographic responses, and decreased macular thickness on optical coherence tomographic testing. Two variants in the PRPF8 gene were identified in the proband, H2309R and IVS41-4G→A. The H2309R mutation segregated with the disease in the family, whereas the IVS41-4G→A variant did not. Conclusions: The severe form of adRP was caused by the PRPF8 H2309R variant, whereas the IVS41-4G→A variant was benign. Clinical Relevance: PRPF8 mutations should be suspected in patients with a type 1 form of adRP. A combination of advanced clinical workup and comprehensive genetic testing is essential for the precise diagnosis of diseases with high genetic heterogeneity such as RP.

Prognosis for splicing factor PRPF8 retinitis pigmentosa, novel mutations and correlation between human and yeast phenotypes

“…Four papers (Kondo, et al, 2003;MartinezGimeno, et al, 2003;van Lith-Verhoeven, et al, 2002;Walia, et al, 2008) provide more detailed descriptions of the phenotype associated with individual mutations but give at best only a limited comparison with clinical findings in other families. Here we present clinical data on a family and two cases with new mutations, a de novo case of a known mutation, additional clinical data on two published families, and an overview of previously published clinical findings in eight further families.…”

“…In addition, published clinical information from eight families are summarised (identified in Table 1 as Dutch (van LithVerhoeven, et al, 2002) Japanese (Kondo, et al, 2003), Spanish1-4 (Martinez-Gimeno, et al, 2003), US1 (Walia, et al, 2008) and US2 (Kojis, et al, 1996). Lastly, clinical information is given for the de novo case (British2) and three new families (British 3, 4 and 5) described herein.…”

“…Legend: NR= non-recordable; VA= visual acuity; CMO= central macular oedema; CF= counting fingers; HM= hand movements; PSCLO= posterior subcapsular lens opacity; PSCC= posterior subcapsular cortical cataract. References; Dutch family (van Lith-Verhoeven, et al, 2002), British 1 (McKie, et al, 2001;, British 2 (described herein), South African (Greenberg, et al, 1994;McKie, et al, 2001), US1 (Walia, et al, 2008), Japanese (Kondo, et al, 2003), Spanish 1-4 (Martinez-Gimeno, et al, 2003), British 3, 4 and 5 (described herein) and US2 (Kojis, et al, 1996). frame-shift 2325fsX2359 (Kondo, et al, 2003) c.6991delG frame-shift E2331fsX2358 (Sullivan, et al, 2006) IVS exon 41/ 42 junction IVS41-4G>A Splice site change (Sullivan, et al, 2006) -Gimeno, et al, 2003) Nucleotide numbering reflects cDNA numbering with +1 corresponding to the A of the ATG translation initiation codon in the reference sequence (accession number NG_009118), according to journal guidelines (www.hgvs.org/mutnomen).…”

“…Mutations in PRPF8 have been described as causing a severe form of dominant RP (Gamundi, et al, 2008;Walia, et al, 2008). However, in contrast to the phenotype for the commoner PRPF31 form of splicing-factor RP, which has been well documented in patients with a variety of mutations (Al-Maghtheh, et al, 1996;Evans, et al, 1995) there has been no published overview of PRPF8-RP phenotype across a range of mutations.…”

CPSF1 mutations are associated with early-onset high myopia and involved in retinal ganglion cell axon projection

“…Of the six probands with CPSF1 mutations in this study, five did not have mutations in other genes known to be associated with genetic eye diseases, but one (HM693) had a c.6980C>T (p.S2327F) variant in PRPF8 , as described in our previous study (34). Mutations in PRPF8 have been associated with autosomal dominant retinitis pigmentosa (adRP) with rod-dominated defects (56,57). However, ERG recordings from individual HM693 showed cone-dominated defects (Supplementary Material, Fig.…”