Autosomal Dominant Retinitis Pigmentosa with Intrafamilial Variability and Incomplete Penetrance in Two Families Carrying Mutations in PRPF8

Retina Autosomal Dominant Retinitis Pigmentosa with Intrafamilial Variability and Incomplete Penetrance in Two Families Carrying Mutations in PRPF8

Ce´cilia G. Maubaret,1,2 Veronika Vaclavik,1,2,3,4,5 Rajarshi Mukhopadhyay,1,2,3 Naushin H. Waseem,1 Amanda Churchill,6 Graham E. Holder,1,3 Anthony T. Moore,1,3 Shomi S. Bhattacharya,1 and Andrew R. Webster1,3

PURPOSE. The aim of this study was to report detailed genotype/ mutation c.6930GϾC (p.R2310S) was found in the second phenotype correlation in two British autosomal dominant ret- family. initis pigmentosa (adRP) families with recently described mu- CONCLUSIONS. This is the first report of marked intrafamilial tations in PRPF8. variability associated with mutations in the PRPF8 gene, in- METHODS. Ten affected members from the two families (ex- cluding incomplete penetrance. PRPF8 mutations should be cluded for PRPF31 mutations) were assessed clinically. Seven suspected in patients with adRP and variable expressivity. (Invest subjects had fundus photography; some had electrophysiology, Ophthalmol Vis Sci. 2011;52:9304–9309) DOI:10.1167/iovs.11- autofluorescence imaging, and visual field testing. Linkage anal- 8372 ysis was performed from genomic DNA in one family. RNA was extracted from lymphocytes of the proband from both families, etinitis pigmentosa (RP) is term used to describe a group of reverse transcribed into cDNA and subsequently screened for Rinherited retinal disorders in which there is degeneration mutations in PRPF8. Segregation of mutations in each family of rod and cone photoreceptors. There is considerable genetic was tested by direct genomic sequencing of the specific exons and phenotypic heterogeneity. Typically the first symptom is carrying the mutation. night blindness reflecting early rod photoreceptor involvement RESULTS. All affected members complained of nyctalopia with and later there is peripheral field loss and ultimately visual loss variable age of onset. In the first family, there was marked due to involvement of cones in the central retina.1 RP is the variation in the clinical phenotype among affected individuals most frequent inherited form of blindness with a prevalence of ranging from severe rod-cone dystrophy to a 67-year-old pa- approximately 1 in 4000.2 The disorder may be inherited as an tient with a normal retinal appearance and mild rod dysfunc- autosomal dominant, autosomal recessive, or X-linked reces- tion on scotopic electroretinography (ERG). The second family sive trait; maternal, mitochondrial inheritance has also been demonstrated similar variability and a history of a nonpenetrant reported.3 RP may result from mutations in more than 45 individual. Linkage analysis in the first family showed strong genes.3 Dominant transmission occurs in approximately one evidence for linkage to markers on chromosome 17p implicat- third of cases and at least 17 genes have been implicated in ing PRPF8 as a candidate gene. A c.6353 CϾT change causing autosomal dominant RP (adRP).4 Three of these genes, PRPF3, a nonconservative missense mutation p.S2118F was found in PRPF8, and PRFP31 encode splicing factors which together exon 38 of PRPF8 by direct sequencing of the cDNA. The account for approximately 15% of families with adRP in the United Kingdom (RM, ARW, personal communication, 2011). There are few detailed descriptions of the clinical pheno- 5 1 type associated with PRPF8 mutation. The present report From the Institute of Ophthalmology, University College London, describes the detailed clinical phenotype in two British families London, United Kingdom; 3Moorfields Eye Hospital, London, United Kingdom; 4Ophthalmology Department, The University Hospitals of with adRP associated with mutations in PRPF8. Geneva (HUG), Geneva, Switzerland; 5Ophthalmology Hospital Jules Gonin, Lausanne, Switzerland; and 6Bristol Eye Hospital, Bristol, United Kingdom. PATIENTS AND METHODS 2These authors contributed equally to the work and should be considered equivalent first authors. The study adhered to the tenets of the Declaration of Helsinki and was Supported by grants from The Foundation Fighting Blindness, approved by the Local Research Ethics Committee. Fight for Sight European Union Grants EVI-GENORET LSHG-CT-2005– 512036 and RETNET MRTN-CT-2003–504003, a grant from Special Clinical Assessment Trustees of Moorfields Eye Hospital, RD Crusaders Foundation via Fight for Sight, National Institute for Health Research Biomedical Research Two families, a six-generation (family 1) and another three-generation Centre for Ophthalmology, Moorfields Eye Hospital, Foundation Fight- (family 2), were ascertained from the inherited eye disease clinic of the ing Blindness (USA), and the British Retinitis Pigmentosa Society. Moorfields Eye Hospital (Fig. 1). Eight members of family 1, seven Submitted for publication August 10, 2011; revised October 12, affected and one mildly symptomatic, underwent ophthalmic exami- 2011; accepted October 13, 2011. nation including best-corrected visual acuity, slit lamp examination and Disclosure: C.G. Maubaret, None; V. Vaclavik, None; R. fundoscopy. Full medical histories were obtained. Color fundus pho- Mukhopadhyay, None; N.H. Waseem, None; A. Churchill, None; tography was performed in five out of eight patients; three had auto- G.E. Holder, None; A.T. Moore, None; S.S. Bhattacharya, None; A.R. Webster, None fluorescence imaging (AF) and spectral-domain optical coherence to- Corresponding author: Rajarshi Mukhopadhyay, Institute of Oph- mography (SD-OCT) and four had Goldmann visual field examination thalmology, UCL, 11-43 Bath Street, EC1V 9EL London, UK; (VF). Four affected members of family 2 were examined and under- [email protected]. went color fundus photography and three had AF and SD-OCT.

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FIGURE 1. Pedigree and the electropherogram of family 1 showing mutation in exon 38 (c.6353 CϾT) (upper panel) and (lower panel) the pedigree and c.6930GϾC mutation in exon 42 of family 2.

Full field electroretinography (ERG) was performed using the In- the families, genomic DNA was sequenced using primers e38F/e39R in ternational Society for Clinical Electrophysiology of Vision (ISCEV) family 1 and e42F/e42R in family 2. DNA from 130 healthy Caucasian standards6 in two of the milder affected members of family 1 (IV.8 and controls (Sigma-Aldrich, Dorset, UK) was sequenced for the two iden- V.12; Fig. 1) and a young (6-year-old) affected (III.2; Fig. 1) from family tified mutations from family 1 and family 2. 2 who underwent a modified pediatric ERG protocol.7

Molecular Genetic Analysis RESULTS After obtaining written consent, blood samples from affected and unaffected family members were collected for DNA and RNA extrac- Clinical Assessment tions. RNA was isolated from lymphocytes of one affected member Family 1. Seven clinically affected members aged between from each family (Trizol; Invitrogen, Paisley, UK), genomic DNA was 37 and 82 years and one mildly symptomatic, obligate carrier extracted using commercially-available kits (Nucleon DNA Isolation Kit (68 years) were assessed. Six affected subjects complained of for Mammalian Blood; Tepnel Life Sciences, Manchester, UK) accord- night blindness as the first symptom. The age of onset of the ing to the manufacturer’s instructions. Microsatellite markers flanking night blindness varied within family members from early child- known genes for adRP were selected from a linkage mapping set (ABI hood (patients V.10, V.11, V.12) to mid-thirties (IV.12). Visual Prism Linkage Mapping Set v 2.5; Applied Biosystems, Foster City, CA) field constriction was reported in late teens in patients III.2 and and additional FAM-labeled microsatellite markers were selected from V.11 and after the age of forty in patient IV.12. Patient IV.8, an 8 the Ensembl database. PCRs were done (Absolute QPCR; Thermo- obligate carrier, reported no problems driving at night or Fisher, Epsom, UK) according to manufacturer’s instructions. The looking at stars in the night sky although had confessed to mild resultant PCR products were loaded in a DNA sequencer (ABI model difficulty in different lighting conditions previously. He did not 3730; Applied Biosystems) and the genotyping calls and Mendelian complain of any visual field constriction. error checks were performed with commercial software (GeneMarker, Best corrected visual acuity (BCVA) in the better eye was version 1.70; Biogene, Cambridgeshire, UK) for linkage analysis. 6/12 or better in five out of seven symptomatic patients. In the 82-year-old female (III.2), BCVA was 6/18 in the right and 6/36 Mutation Screening in the left eye while in a 59-year-old male (IV.2), it was hand cDNA was synthesized from leukocyte RNA (patient IV.2 in family 1 movements right and 6/18 left eye. and II.2 in family 2) using reverse transcriptase (Superscript III Reverse Bilateral subcapsular cataract was observed in patients III.2 Transcriptase; Invitrogen) according to manufacturer’s instructions. at a young age, IV.2 (age 34 years), and V.11 (age 33 years). In Mutation analysis was performed by Sanger sequencing of the cDNA all patients fundoscopy revealed attenuated retinal vessels, pale using a terminator sequencing kit (BigDye ver 3.1; Life Technologies, optic nerve head and variable degrees of diffuse bone spicule- Paisley, UK) on the ABI 3730 machine (Applied Biosystems). cDNA like pigment clumping within the neurosensory retina sequences obtained for patient IV.2 and II.2 were compared with the (Fig. 2A). Asteroid hyalosis was observed in the left eye of reference sequence of PRPF8 from the Ensembl database.8 Primers patient IV.12. Patient V.11 had bilateral optic nerve drusen. used for PCR and sequencing are described in Table 2 of Towns et al.5 Patient IV.2 developed Coats-like retinal telangiectasia in his Exons and nucleotides were numbered according to OMIM (Online right retinal periphery resulting in a vitreous hemorrhage when Mendelian Inheritance in Man; http://www.ncbi.nlm.nih.gov/Omim/ aged 34 years. Patient IV.12 had an episode of angle closure provided in the public domain by the National Center for Biotechnol- glaucoma at 41 years of age. Cystoid macular edema of various ogy Information, Bethesda, MD) ID 607300. For the other members of degrees was observed in four symptomatic patients (IV.2, V.10,

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FIGURE 2. Variability of phenotype of PRPF8 retinitis pigmentosa. (A) Family 1; (B) family 2. (A1) Right fundus of 60-year-old male shows extensive intraretinal pigmentation with mid-peripheral and macular atrophy. Spectral domain OCT shows areas of outer retinal atrophy in right (A2) and left eye (A3). (A4, A5) Right fundus andAF of a 51-year-old female shows little intraretinal pigmentary deposition but widespread retinal pigment epithelial atrophy. (A6, A7) The right fundus of a 38-year-old male shows patchy intraretinal pigmentation with AF showing a small peri-foveal hyperfluorescent ring. (B) Family 2; (B1, B2) show extensive RPE atrophy involving the macula in the the fundus and AF of a 49-year-old male. His daughters showed little pigmentary deposition in their fundi (B3, B5) but hyperfluorescent rings in AF at age 15 and 11 years of age respectively (B4, B6). (C) Asymptomatic: fundus photographs, autofluorescence, spectral-domain OCT, and Goldmann visual fields of asymptomatic individual IV.8 of family 1 showing relative preservation of normal structure and function at 63 years of age. OCT of the right eye shows the presence of an epiretinal membrane causing flattening of the foveal depression.

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V.11, and V.12). Individual IV.8 had a normal retinal appear- was 6/10 right eye; 6/5 left eye. The youngest daughter (III.3) ance (Fig. 2C). was noted to be night blind in the first decade and at age 11 AF imaging revealed extensive peripheral atrophy in two years had BCVA of 6/15 in both right and left eyes. According affected individuals with a small peri-foveal ring of increased to reports from her sons, the deceased grandmother of the two autofluorescence (Fig. 2A). OCT showed preserved outer reti- affected females (I.2) had no visual symptoms when she died at nal structure in the area delineated by the ring of hyperauto- the age of 69 years. fluorescence (Fig. 2A). In another patient (IV.2), OCT showed All symptomatic family members examined showed severe disruption of the outer retinal structure in the fovea (Fig. 2A). attenuation of arterioles, pale optic discs, and sparse intrareti- AF and OCT of the only mildly symptomatic obligate carrier nal pigment migration (Fig. 2B). AF in patient II.1 showed (IV.8) (Fig. 2C) were normal. peripheral and central macular atrophy, while there was pres- Goldman perimetry showed a variable degree of visual field ervation of central macula with perifoveal hyperautofluores- loss with patient V.12 retaining approximately 50° of horizon- cent ring in the two young females (III.2 and III.3) (Fig. 2B). AF tal visual field in the better eye with the biggest and brightest and OCT revealed bilateral macular edema in both III.2 and target (V4e) at 34 years of age while V.10 had near normal III.3 with the younger more affected (Fig. 2B). OCT of II.1 fields at 37 years of age. Subject IV.2 had a small central field of showed central macular atrophy. approximately 15° at 38 years of age with retention of a Electrophysiological assessment of III.2 at 6 years of age temporal island of preserved field. Individual IV.8 had normal using pediatric protocols revealed severe photoreceptor dys- visual fields at 63 years of age (Fig. 2C). function with undetectable waveforms (Fig. 3B). Electrophysiological testing of the patient (IV.8) who complained of only mild contrast adjustment showed mildly abnor- Mutational Screening mal rod photoreceptor function (rod specific ERGs were nor- Family 1. Linkage analysis with flanking microsatellite mal but bright flash [DA 11.0] a-wave was mildly reduced). markers to all known adRP loci showed strong evidence for Cone ERGs were normal (Fig. 3A). Subjects V.10 and V.12 had linkage at the RP13 locus (markers D17S849, D17S831, only residual detectable rod and cone ERGs in keeping with a D17S1840, D17S1574, and D17S525). Because PRPF8 is the severe rod-cone dystrophy (data not shown). gene implicated in RP13, it was initially decided to directly Family 2. The proband, a 35-year-old man (Fig. 1, lower sequence exon 42 as all published mutations have been panel, II.2), had night vision problems from early childhood found in this exon. No variant was found by direct sequenc- and was diagnosed with RP in his late teens. He later developed ing of the proband IV.2. Therefore, RNA from IV.2 was deterioration of central vision and when examined aged 35 extracted, reverse transcribed, and PRPF8 cDNA was di- years, right eye BCVA was 6/24 with hand movements in the rectly sequenced allowing for a quick investigation of pos- left eye. At that time his Esterman supra-threshold bilateral sible splicing defect and/or exonic mutation. The variant visual fields were reduced to Ͻ5° (data not shown). He devel- c.6353 CϾT, was identified in exon 38 in a heterozygous oped bilateral subcapsular cataracts in his mid-twenties. His state (Fig. 1, upper panel). Direct sequencing of the PRPF8 half-brother (II.1), sharing the same mother, was also affected exon 38 from the genomic DNA of the whole family revealed and had early onset of subcapsular cataracts for which he that all the affected patients, and the one mildly symptom- underwent bilateral cataract surgery. His BCVA at 48 years of atic carrier harbored this change, which was not present in age was 3/60 right and left. His older daughter (III.2) devel- unaffected family members. The mutation c.6353 CϾT oped night blindness in early childhood. BCVA at age 15 years (p.S2118F) was not found in 130 unrelated controls from the

FIGURE 3. Electrophysiology of affected individuals. (A) ISCEV standard ERGs of patient IV.8 (see Fig. 2C 63 years of age, asymptomatic) show subnormal DA 11.0 a-wave ampli- tude. (B) ERGs of patient III.2 of family 2 (6 years of age, symptomatic) show severe generalized loss of both rod and cone photoreceptor function.

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same ethnic origin indicating that this change is likely to be There is a history of incomplete penetrance in two individ- causative of the disorder in this family. uals in the second family, but neither was available for exam- Family 2. The entire cDNA of affected proband (II.2) was ination. The mutations p.R2310K9,11 and p.R2310G9,10 have sequenced and the mutation c.6930GϾC (Fig. 1, lower panel) previously been reported and suggests that c.6930GϾC leading to p.R2310S missense change in the protein was iden- (R2310S) in exon 42 is a hot spot for mutation. tified in exon 42. The same variant was present in all affected PRPF8, PRPF3, and PRPF31 genes are involved in the family members and was not found in 130 control individuals. assembly and function of the spliceosome, which clips introns out of pre-mRNA.20 The gene PRPF8 encodes a large and highly conserved nuclear protein21 which stimulates a heli- 22 DISCUSSION case, Brr2, required for activation of the spliceosome. PRPF8 mutations which cause adRP inhibit this function. More than This report describes the detailed phenotype of affected mem- 15 different mutations, most situated within exon 42 of bers of a large British family carrying the missense PRPF8 PRPF89–13, are associated with RP and presumably inhibit the mutation c.6353 CϾT (p.S2118F) in exon 38 recently reported interaction of the PRPF8 protein with Brr2. The only detected by Towns et al.5 All previous PRPF8 mutations had been mutation in PRPF8 outside exon 42 is p.S2118F, which was reported to occur in exon 42 of the gene.9–13 Mutations in reported recently, occurring in family 2 of this report.5 This PRPF8 gene are rare, accounting for 2%–3% of patients with nonconservative amino acid change is predicted to cause sig- adRP in Spanish and American studies,1,3,10,14 and 3.5% in a nificant alteration to the structure and function of the PRPF8 large United Kingdom cohort (RM, ARW, unpublished obser- protein. vations, 2011). These percentages are likely to be underesti- The function of the C-terminal of PRPF8 protein has been mates given the current restriction of screening to exon 42 of investigated using various methods by different laboratories. the gene. Grainger and Beggs21 suggested that the nine RP13 missense Previous reports have documented a severe form of RP in mutations reported in exon 42 of PRPF8 affect seven very British, Spanish, Dutch, and African American families, with highly conserved amino acid residues indicating that those mutations in exon 42 of PRPF810–13,15. The previous pheno- residues have a conserved function which is altered in case of type descriptions were consistent with an infantile onset of mutation. Those nine amino acids belong to the region of night blindness, followed by visual field loss a few years later. yPrp8p that interacts with Brr2p, one of the spliceosomal RNA All the published adult patients have unrecordable ERG values helicases, and is close to the prp8–1 (G2347D) mutation, and the rod function in affected pediatric population is se- which ablates the binding of C-terminal yPrp8 peptides by verely abnormal.10,11,13,15 The phenotype is relatively uniform yBrr2p in vitro.23 By yeast two-hybrid, Fan et al.24 have dem- and there is no evidence of variability or incomplete pen- onstrated that C-terminal 94-amino acid region of hPRPF8 in- etrance. The present study reveals a high degree of intrafamilial teracts with the multifunctional plasminogen activator inhibi- phenotypic variability. The age of onset of night blindness tor type-2 protein (PAI-2). Therefore, it is reasonable to assume varied from early childhood to late thirties. One 67-year-old that the interaction PRPF8/PAI-2 could also be altered in RP13 individual heterozygous for the c.6353 CϾT (p.S2118F) muta- patients. tion who was only mildly symptomatic, had a completely Recently, two different groups have established indepen- normal fundus appearance. Macular edema was observed in dently the crystal structure of PRPF8.25,26 Both groups pro- four out of seven patients (IV.2, V.10, V.11, V.12) of family 1 posed that the C-terminal domain of PRPF8 including the MPN and two out of four patients (III.2 and III.3) in family 2 and (Mpr-1, Pad-1, N-terminal) domain is an interaction domain. seems to occur with higher frequency in patients with a PRPF8 They suggest that the reported residues mutated in RP13 con- mutation than other forms of adRP.11–13,15 stitute a binding surface between PRPF8 and other partner(s) AF imaging in symptomatic patients with relative preserva- and the disruption of this interaction provides a plausible tion of visual acuity, when available, revealed a ring of in- molecular mechanism for RP13. It is notable that exon 38 creased autofluorescence surrounding the central macula (Fig. encodes a part of the MPN domain of PRPF8 and S2118 is part 2). Hyperfluorescent rings of various types are observed in RP of an ␣1 helix which is may be altered by the mutation in the or Leber congenital amaurosis (usually surrounding healthy present report. macula) and cone or cone-rod dystrophy or X-linked retinos- To conclude, this is the first report of marked intrafamilial chisis (usually surrounding dystrophic macula).16 However, in variation and nonpenetrance associated with two PRPF8 mu- primary RPE retinal dystrophies, such as those caused by mutations: c.6353 CϾT (p. S2118F) in exon 38 and c.6930GϾC tations in MERTK or RPE65, such rings have not been de- (p.R2310S) in exon 42. The data suggest that all exons of scribed.17,18 Furthermore, SD-OCT images in affected patients PRPF8 should be screened in families with adRP and incom- demonstrate an intact hyperreflective layer at the junction of plete penetrance. The important role of electrophysiological dystrophic retina and choroid which might represent intact assessment is noted. The findings extend the range of pheno- RPE-Bruch’s membrane complex. However, in the mouse types seen in association with PRPF8 gene mutations and model there is evidence of defective RPE function.19 It is provide important information to assist the management of possible that human PRPF8 retinopathy may have thus differ- families in whom this form of adRP is suspected. ent pathophysiology with relative late demise of RPE. The ERG in the mildly symptomatic obligate carrier showed Acknowledgments a DA 0.01 rod ERG within the normal range but a subnormal DA 11.0 bright flash ERG a-wave. Cone full-field ERGs and The authors thank the patients who participated in the study. pattern ERGs were normal. The consequences of this mutation, which in other family members caused legal blindness, were those of minor rod photoreceptor function. Affected status was References not evident from fundus examination or perimetry. This sug- 1. Daiger SP, Bowne SJ, Sullivan LS. Perspective on genes and muta- gests caution in reassuring members of families with PRPF8- tions causing retinitis pigmentosa. Arch Ophthalmol. 2007;125: related disease of their unaffected status and confirms the 151–158. importance of electroretinography in the detection of subclin- 2. Berson EL. Retinitis pigmentosa. The Friedenwald Lecture. Invest ical disease. Ophthalmol Vis Sci. 1993;34:1659–1676.

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