Mutations in RPGR and RP2 Account for 15% of Males with
Simplex Retinal Degenerative Disease
Kari Branham,1Mohammad Othman,1Matthew Brumm,1Athanasios J. Karoukis,1
Pelin Atmaca-Sonmez,1Beverly M. Yashar,2Sharon B. Schwartz,3Niamh B. Stover,4
Karmen Trzupek,4Dianna Wheaton,5Barbara Jennings,6Maria Laura Ciccarelli,7
K. Thiran Jayasundera,1Richard A. Lewis,8David Birch,5Jean Bennett,9Paul A. Sieving,1,10
Sten Andreasson,11Jacque L. Duncan,12Gerald A. Fishman,13Alessandro Iannaccone,6
Richard G. Weleber,4Samuel G. Jacobson,3John R. Heckenlively,*,1and Anand Swaroop*,1,2,10
PURPOSE. To determine the proportion of male patients
presenting simplex retinal degenerative disease (RD: retinitis
pigmentosa [RP] or cone/cone-rod dystrophy [COD/CORD])
with mutations in the X-linked retinal degeneration genes
RPGR and RP2.
METHODS. Simplex males were defined as patients with no
known affected family members. Patients were excluded if
they had a family history of parental consanguinity. Blood
samples from a total of 214 simplex males with a diagnosis of
retinal degeneration were collected for genetic analysis. The
patients were screened for mutations in RPGR and RP2 by
direct sequencing of PCR-amplified genomic DNA.
RESULTS. We identified pathogenic mutations in 32 of the 214
patients screened (15%). Of the 29 patients with a diagnosis of
COD/CORD, four mutations were identified in the ORF15
mutational hotspot of the RPGR gene. Of the 185 RP patients,
three patients had mutations in RP2 and 25 had RPGR
mutations (including 12 in the ORF15 region).
CONCLUSIONS. This study represents mutation screening of
RPGR and RP2 in the largest cohort, to date, of simplex males
affected with RP or COD/CORD. Our results demonstrate a
substantial contribution of RPGR mutations to retinal degen-
erations, and in particular, to simplex RP. Based on our
findings, we suggest that RPGR should be considered as a first
tier gene for screening isolated males with retinal degenera-
tion. (Invest Ophthalmol Vis Sci. 2012;53:8232–8237) DOI:
progressive photoreceptor degenerative disease leading to
vision loss.1RP affects approximately 1 in 4000 individuals in
the United States and other developed countries.1–3Autosomal
dominant, autosomal recessive, and X-linked forms of RP exist,
and more than 60 genes have been identified as the cause of
nonsyndromic disease (https://sph.uth.tmc.edu/retnet/disease.
htm). Clinical and population-based studies have shown that a
substantial portion of RP patients are isolates or ‘‘simplex,’’1,3–6
that is, patients with no family history of disease. These
simplex cases pose a dilemma for clinicians who are ordering
genetic testing for diagnosis and inheritance counseling or for
clinical management of patients and respective families. Prior
to the era of molecular genetic testing, isolated cases were
considered by default to be of autosomal recessive inheritance,
and the families were counseled that there was a negligible
recurrence risk for future generations to be affected. However,
such cases might represent de novo autosomal dominant or X-
linked disease. Furthermore, as gene-based therapies are being
translated to treatment, determining the genetic basis of a
patient’s clinical phenotype is expected to become an
important standard of care for disease management.7
etinitis pigmentosa (RP) is the clinical diagnosis for a large
group of inherited retinal disorders, characterized by
From the1Department of Ophthalmology and Visual Sciences,
University of Michigan, Kellogg Eye Center, Ann Arbor, Michigan;
2Department of Human Genetics, University of Michigan, Ann Arbor,
Michigan;3Scheie Eye Institute, University of Pennsylvania, Phila-
4Casey Eye Institute, Oregon Health &
Science University, Portland, Oregon;
Southwest, Dallas, Texas;
6Hamilton Eye Institute, University of
Tennessee Health Science Center, Memphis, Tennessee;7Division of
Ophthalmology, Israelitic Hospital, Rome, Italy;
Ophthalmology, Cullen Eye Institute, Baylor College of Medicine,
9Department of Ophthalmology, University of
Pennsylvania School of Medicine, Philadelphia, Pennsylvania;
10National Eye Institute, National Institutes of Health, Bethesda,
11Department of Ophthalmology, University of Lund
Medical School, Lund, Sweden;12Department of Ophthalmology,
University of California-San Francisco, San Francisco, California; and
the13Department of Ophthalmology, University of Illinois, Chicago,
Supported by intramural research program of the National Eye
Institute ZO1 EY000473 (AS), NIH-EY007961 (AS), The Foundation
Fighting Blindness (AS, DB, GAF, JB, JLD, JRH, SGJ, RGW), Harold F.
Falls Collegiate Professorship (AS), unrestricted grants from Re-
search to Prevent Blindness, New York, New York to the W.K.
Kellogg Eye Center, UCSF Department of Ophthalmology, Cullen Eye
Institute, and Hamilton Eye Institute. RAL is a Senior Scientific
Investigator of RPB.
Submitted for publication September 25, 2012; revised October
26, 2012; accepted November 6, 2012.
Disclosure: K. Branham, None; M. Othman, None; M.
Brumm, None; A.J. Karoukis, None; P. Atmaca-Sonmez, None;
B.M. Yashar, None; S.B. Schwartz, None; N.B. Stover, None; K.
Trzupek, None; D. Wheaton, None; B. Jennings, None; M.L.
Ciccarelli, None; K.T. Jayasundera, None; R.A. Lewis, None; D.
Birch, None; J. Bennett, None; P.A. Sieving, None; S. Andreas-
son, None; J.L. Duncan, None; G.A. Fishman, None; A.
Iannaccone, None; R.G. Weleber, None; S.G. Jacobson, None;
J.R. Heckenlively, None; A. Swaroop, None
*Each of the following is a corresponding author: Anand
Swaroop, Neurobiology Neurodegeneration & Repair Laboratory
(N-NRL), National Eye Institute, National Institutes of Health Bldg 6/
338, 6 Center Drive, MSC 0610, Bethesda, MD 20892-0610;
John R. Heckenlively, Department of Ophthalmology, W.K.
Kellogg Eye Center, University of Michigan, 1000 Wall Street, Ann
Arbor, MI 48105; firstname.lastname@example.org.
5Retina Foundation of the
Investigative Ophthalmology & Visual Science, December 2012, Vol. 53, No. 13
Copyright 2012 The Association for Research in Vision and Ophthalmology, Inc.
X-linked RP (XLRP) is estimated to comprise 6% to 20% of
all RP.3,5,6,8,9XLRP males typically show a rapid course of
vision loss, with a significant proportion progressing to legal
blindness by 40 years of age. Affected males usually present
with night blindness and decreased or nonrecordable ERG
responses in the first or second decade. Some XLRP patients
exhibit high myopia and decreased visual acuity even at an
early age.10Heterozygous carrier females also manifest a range
of phenotypes, varying from asymptomatic to mild fundus
changes and pigment migration to some females showing a
severe phenotype.8,11Although the presence of a tapetal-like
reflex has been described as indicative of carrier status, this is
not universally detected.8
Two principal genes, RP2 and RPGR, have been identified
as the primary causative genes in XLRP. One additional gene,
OFD1, has been identified recently to have changes associated
with XLRP in a single family.12Two additional chromosomal
loci, RP2413and RP6,14have also been associated with XLRP.
RP2 is mutated in 7% to 18% of XLRP,15–18whereas RPGR
mutations are observed in 56% to 90% of patients with X-linked
disease.14,19–22Though a substantial fraction of RPGR muta-
tions are detected in the RCC1 homology domain, the fraction
of XLRP patients carrying identifiable mutations was lower
than expected before the discovery of the mutation hotspot
region ORF15. This 15-exon transcript is highly expressed in
the retina and is mutated in 30% to 63% of males with
XLRP.15,23–30Mutations in RPGR are associated with XLRP, as
well as with X-linked cone-dystrophy (COD),29,31cone rod
dystrophy (CORD),32,33and an atrophic form of macular
degeneration.34Patients with COD or CORD may present with
decreased visual acuity, central vision loss, and decreased color
vision. ERG responses are abnormal; the photopic system is
more severely affected than the scotopic ERG responses.35
Patients with RPGR mutations have also been reported to have
nonocular phenotypes, such as hearing loss, recurrent
respiratory infections, and primary ciliary dyskensis.30,36,37
Simplex patients comprise a substantial proportion, ranging
from 41% to 63%, of all RP patients.1,4,5,38,39In two of the
reported cohorts, males comprised 51% to 59% of the simplex
patients.3,4Previous mutation screening studies included 5 to
55 simplex males and identified XLRP mutation rates of 0% to
32%.15,26,28,40,41However, there was much variation in the
ascertainment for these samples, and some of the cohorts
included only those with presumed X-linked mutations based
on clinical presentation of the patients. We examined a large
cohort of simplex males for mutations in the X-linked retinal
dystrophy (RD) genes RP2 and RPGR. Our genetic analyses
argue in favor of including RPGR as a candidate gene for initial
mutation screening of male patients with isolated RP.
A cohort of simplex males diagnosed with nonsyndromic RP (N¼185)
or COD/CORD (N ¼ 29) was collected for mutation analysis. In a
previous study, we included 55 simplex males in our screening.15
Individuals from this initial screening were also included in this current
study if their pedigrees still met the study parameters (as defined
below). Two hundred nine subjects were diagnosed by clinical
examination, visual fields, and electroretinography. Subjects presented
with a range of clinical presentations from early onset to later ages of
onset of RP/COD/CORD. They were enrolled from ophthalmology
clinics primarily in the United States, and a few were collected in
Europe (Italy and Sweden). Five patients were referred to the study
from a registry with self-reported inherited retinal disease. Informed
consent was obtained from all subjects. Institutional Review Board of
the University of Michigan approved the study protocol, and the
research adhered to the tenets of the Declaration of Helsinki.
Pedigree information was gathered and analyzed for all patients.
Subjects with a history of consanguinity or those whose family history
was unknown (i.e., adopted) were excluded from the analysis. Simplex
males were defined as subjects who had no family members affected
with RP, COD, or CORD. Pedigrees were grouped into two different
categories. In Category A, there were no additional reports of any
female family members with any symptoms consistent with RP, COD,
or CORD. In Category B, one or more females in the family reported
having some symptoms, such as night blindness or color vision
difficulties, which could be consistent with a carrier state for XLRP.
However, none of these females was diagnosed as having RP, COD, or
DNA was extracted from lymphocytes with Qiagen whole blood kits
(Qiagen, Valencia, CA). Methods for RP2 mutational analysis were
reported previously.10For RPGR mutation screening, the primer
sequences were reported previously for the analysis of exons 1 through
1925and ORF15.32Accuprime high fidelity Taq polymerase (Invitrogen,
Grand Island, NY) was used to amplify various RPGR exons. PCR setup
conditions were 100 ng of DNA per reaction, 2.5 lL of 103Accuprime
HF buffer, 0.5 lL of 10 lmol/L of each the forward and reverse primers,
0.1 lL of Accuprime HF Taq polymerase (5 U/lL) and water to 25-lL
reaction volume. PCR conditions for all RPGR exons except RPGR-
ORF15 were 948C for 2 minutes followed by 10 cycles at 928C for 20
seconds, 568C for 30 seconds, and 688C for 30 seconds; followed by 25
cycles at 928C for 20 seconds, 608C for 30 seconds, and 688C for 30
seconds; followed by 10 minutes of extension at 688C and hold at 48C.
RPGR-ORF15 exon was amplified by two sets of primers. Exon 15_1F
primers and 4R amplified ~ 2 kb fragments, while the purine rich
region was amplified with 3F/3R primers (see https://sph.uth.tmc.edu/
retnet/disease.htm for the primers location and sequences) to amplify
~ 1 kb fragments. The PCR conditions were similar to other exons
except that following annealing at 568C and 608C, extensions at 688C
were for 1 and 2.5 minutes for 3F/3R and 1F/4R fragments,
respectively. Aliquots of the amplified PCR products were analyzed
using 1% agarose gels, viewed using UVP bioimaging system (UVP,
Upland, CA), and submitted to the University of Michigan Medical
School Sequencing Core.
Mutational Data Analysis
Sequences were analyzed by two independent investigators with
Sequencher (Gene Code Corporation, Ann Arbor, MI). All identified
mutations were validated by another independent PCR analysis of each
sample. Once a mutation was identified, additional screening was not
performed. For RP2 and RPGR exons 1 through 19, missense,
nonsense, and splice site mutations as well as deletions were
considered causative if they had been reported previously as
mutations, if they were not published previously as polymorphisms,
or if they were not detected in 96 male controls. Missense mutations
were also analyzed for pathogenicity by the Polyphen and SIFT
Programs. In ORF15, only nonsense and frame-shift mutations were
considered disease causing.
Among the 185 subjects with RP, mutations were identified in
28 patients; of these, analyses of samples from three patients
revealed mutations in RP2, 13 in RPGR exons 1 through 14,
and 12 in the RPGR ORF15 region (Table 1). Of the 29 subjects
with COD/CORD, four mutations were identified in ORF15. As
IOVS, December 2012, Vol. 53, No. 13
X-Linked Mutations in Simplex Males 8233
reported in other studies of patients with COD/CORD,26,31–33
these mutations were located towards the 30end of ORF15. No
RP2 mutations were detected in subjects with COD/CORD.
Mutations were identified in 10.7% (19/177) of Category A
patients and 35.1% (13/37) of Category B patients. We found
that 15.1% of simplex RP males and 13.8% of simplex COD/
CORD males had mutations in the two XLRP genes (25/28
being in RPGR).
Of the three RP2 mutations, two were small deletions (one
being novel) and the third was a missense change that was
predicted to be damaging by both Polyphen and SIFT (Table 2).
An additional change (p.Thr87Ile) was considered originally to
be a disease-causing mutation10because it was not detected in
96 male controls and has not been identified as a variant on the
Exome Variant Server. However, analysis with pathogenicity
programs Polyphen and SIFT consider the change to be a
tolerated or benign variant, and we are now considering this
change to be a variant of unknown significance. RPGR
mutations included three missense, four splice site, three
deletions, and two nonsense mutations; six of the identified
mutations were novel (Fig.). In ORF15, eight frame-shift
mutations and five nonsense mutations were identified; nine
of these have not been reported previously. Each mutation was
detected in one patient each, with the exception of c.
2236_2237delGA which was identified in four patients and
c.154G>T which was present in two patients.
In our initial XLRP screening cohort,15we analyzed 234
families including 55 subjects who were the only affected
males in their family with RP yet believed to be X-linked
because of the clinical presentation of an early onset of severe
disease. Of these, 16 subjects had mutations in RPGR or RP2,
with an overall mutation rate of 29%; 5% of the subjects carried
mutations in RP2, 9% in RPGR exons 1 through 14, and 15% in
Simplex Males with RPGR or RP2 Mutations
Total ScreenedRP2RPGR 1–15 RPGR ORF15Total with MutationsP Value
Nature of Mutations Identified in the RP2 (AJ007590) and RPGR (NM_001034853.1) Genes
DiagnosisExon Nucleotide ProteinReference
c. 8 G>C
c. 409_411 del ATT
c. 803 del A
Jayasundera et al.10
Breuer et al.15
c. 28þ2 T>G
c. 154 G>T
c. 155-2 A>G
c. 173delT; 177delT
c. 469þ2 T>A
c. 869 del A
c. 934 þ1 G>A
c. 1216_1217 del CT
c. 1345 C>T
c. 1348 T>C
c. 1699 A>T
c. 2088 del A
c. 2227 G>T
c. 2234_2237 del GAGA
c. 2236_2237 del GA
c. 2296_2299 del GGAG
c. 2384del A
c. 2442_2445 del AGAG
c. 2509 G>T
c. 2614 G>T
c. 2893 G>T
c. 2965 G>T
c. 3308_3309 del AT
Meindl et al.25
Miano et al.48
Buraczynska et al.49
Miano et al.48
Bader et al.23
Breuer et al.15
Breuer et al.15
Vervoort et al.29
Breuer et al.15
Vervoort et al.29
8234Branham et al.
IOVS, December 2012, Vol. 53, No. 13
ORF15. A subsequent study screened 187 male patients for
RP2 and RPGR; of these, 30 simplex patients suspected of
having XLRP (based on visual acuity and myopia) were
screened and 7% showed mutations in RP2, 3% in RPGR
exons 1 through 14, and 3% in ORF15.28A more recent study
of 127 French families included 25 isolated males suspected of
XLRP based on early onset, rapid progression, and subnormal
visual acuity.26In this group, 4% of the patients had mutations
in RP2, 4% in RPGR exons 1 through 14, and 24% in RPGR
ORF15. Another study of 37 families with RP, including five
patients with no family history, found no X-linked mutations
among the simplex subjects.40Finally, 141 families with
possible X-linked inheritance and 39 simplex males were
screened for mutations in RP2 and RPGR, but no mutations
were found in the simplex males.41In summary, these previous
studies vary in their detection rates from 0% to 32%. The
studies with the higher detection rates specifically selected for
simplex males with suspected X-linked inheritance based on
severity or clinical features of disease.15,26,28The two studies
with no reported mutations in X-linked genes did not select the
patients based on the phenotype.40,41These studies were also
relatively small and varied in the countries of origin for their
patient ascertainment. All these factors could contribute to
observed variations in detection rates.
The current study in 214 simplex RD males reports the
largest screening to date of X-linked mutations. The phenotype
of our population varied and included patients with both early
and late onset disease. In our cohort, we identified mutations
in 15% of simplex RP and COD/CORD patients. In the
subcategory of families with one or more female family
members reporting history of decreased vision/night vision
problems, our mutation detection rate was as high as 35%. We
would therefore like to emphasize the importance of taking a
targeted family history when making decisions about genetic
testing and care.
An isolated case of retinal degeneration may be caused by
an autosomal recessive, autosomal dominant (de novo and/or a
family with reduced penetrance), or X-linked gene mutation.
When clinicians are presented with an isolated male, clinical
information may in some cases provide clues to the inheritance
pattern. In others, examination of at-risk female(s) may identify
a distinctive carrier phenotype in an X-linked disorder.
However, in many instances, clinical data are not useful to
determine the genetic basis of the disease. Therefore, the
identification of the genetic defect should be an integral part of
clinical management for retinal degeneration patients, in order
to provide genetic counseling for recurrence risk to parents,
offspring, and siblings. Moreover, with the success of gene-
based treatment(s) for human RPE65 disease42,43and with
new possibilities for many retinal and macular diseases,
including those caused by RPGR mutations,7the knowledge
of the underlying gene defect will be valuable to determine
which trials a patient might be eligible for in the future. The
relatively high X-linked gene mutation frequency identified in
this study strongly argues for characterizing the underlying
cause of RP in simplex male patients.
Our study has important implications for the likely
prevalence of X-linked mutations among simplex RD males.
To determine the genetic cause in an isolated case, a retina
clinician or geneticist is often presented with difficulty in
formulating the appropriate plan of action for ordering genetic
tests. Likely candidate genes for mutation screening of isolated
nonsyndromic RP patients are 34 genes that have been
identified for autosomal recessive RP (http://www.sph.uth.
tmc.edu/Retnet/). Notably, USH2A gene mutations have been
identified as being responsible for 7% to 23% of nonsyndromic
ARRP44–46and, therefore, comprise one of the major causes of
isolated RP. If we take into account that 50% to 60% of all RP
are simplex cases, USH2A would become probably the most
common cause of RP in the United States.44We should also
emphasize the importance of ethnicity in guiding the genetic
testing of simplex RP patients, as demonstrated by the
presence of founder mutations in Ashkenazi Jewish patients.47
The identification of mutations in 15% of the simplex male RD
patients, reported here, would make RPGR a major cause of RP
and CORD. Therefore, we suggest that RPGR should be
included as a first tier gene in the screening strategy for
simplex males with retinal degenerative disease.
We are grateful to patients, their family members, and numerous
clinical colleagues for assistance in the study.
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