Pigmented Paravenous Chorioretinal Atrophy Is
Associated with a Mutation within the Crumbs Homolog
1 (CRB1) Gene
Gareth J. McKay,1Stephen Clarke,1Jason A. Davis,2David A. C. Simpson,1and
PURPOSE. Pigmented paravenous chorioretinal atrophy (PPCRA)
is an unusual retinal degeneration characterized by accumula-
tion of pigmentation along retinal veins. The purpose of this
study was to describe the phenotype of a family with PPCRA,
determine the mode of inheritance, and identify the causal
METHODS. Ophthalmic examination was performed on seven
family members and serially detailed in the proband over a
3-year period. Blood samples were collected and DNA ex-
tracted. All 12 coding exons and the 5? promoter region of the
crumbs homologue 1 (CRB1) gene were PCR amplified and
DNA sequenced. In silico homology modeling was performed
on the mutated protein domain.
RESULTS. Subtle symmetrical chorioretinal atrophy in the in-
ferior quadrant was the earliest clinical sign detectable
within this family. Paravenous pigmentation occurred ini-
tially in the far periphery, progressing centrally, with atro-
phy later becoming more widespread, involving the nasal,
then the temporal, and finally the upper quadrant. A novel,
dominant Val162Met mutation within the fourth EGF-like
domain of CRB1 cosegregates with the PPCRA phenotype. It
is thought to affect domain structure, because codon 162 is
involved in hydrogen bonding between the antiparallel
?-strands of the major ?-sheet, causing sufficient perturba-
tion of the backbone that the domain-stabilizing hydrogen
bond does not form or is weakened.
CONCLUSIONS. PPCRA was dominantly inherited in this family,
but exhibited variable expressivity. Males are more likely to
exhibit a severe phenotype, whereas females may remain vir-
tually asymptomatic even in later years. The PPCRA phenotype
is associated with a Val162Met mutation in CRB1 which is
likely to affect the structure of the CRB1 protein. (Invest
Ophthalmol Vis Sci. 2005;46:322–328) DOI:10.1167/iovs.04-
accumulation of bone corpuscle pigmentation along the retinal
veins.1Patients are often asymptomatic, and the diagnosis is
based on a characteristic fundus appearance, usually during
routine ophthalmic examination. PPCRA was first reported in a
47-year-old man in whom alopecia areata developed and in
whom there was the incidental finding of a bilateral and pecu-
liar fundus appearance, the characteristics of which have since
been considered typical of the disease.2Considerable variabil-
ity in the extent and degree to which the retina is affected has
been reported,3–5with the course of retinal degeneration un-
predictable. It has been suggested6that PPCRA differs from RP
in the absence of night blindness, minimal ERG abnormalities
and its distinctive fundal appearance. However, other investi-
gations have reported night blindness in association with
PPCRA.7We provide a detailed clinical report of the PPCRA
phenotype within an affected family.
The cause of PPCRA is unknown, with some suggesting that
PPCRA is a primary retinal degenerative disease,8and others
reporting a congenital origin.3,5,9,10Of the 90 previously re-
ported cases, 80 have been in male patients and have mostly
been determined to be sporadic.11Previously, a mildly af-
fected, asymptomatic 54-year-old mother received a diagnosis
of PPCRA, along with her mildly affected daughter and severely
affected 28-year-old son (proband).5Dominant or X-linked re-
cessive modes of inheritance were postulated. Unfortunately,
the investigators were unable to ascertain fully the mode of
inheritance because of the restricted number of family mem-
bers that they were able to examine. Descriptions of other
families, however, suggested a dominant mode of inheri-
tance.9,10Doubt, therefore, surrounds the nature of the inher-
itance pattern of this disorder.
After a screening involving several genes known to be
associated with retinal degeneration, we identified a single
nucleotide variation within the CRB1 gene in the proband. In
the present study, the CRB1 genotype was investigated in the
whole family. Mutations in the CRB1 gene (OMIM 604210;
Online Mendalian Inheritance in Man, http://www.ncbi.nlm.
nih.gov/Omim/ provided in the public domain by the National
Center for Biotechnology Information, Bethesda, MD) have
been described previously in a severe, autosomal recessive
form of RP, designated RP12 (OMIM 600105).12–14RP12 is
usually characterized by preserved para-arteriolar retinal pig-
ment epithelium (PPRPE) in the early-to-middle stages of the
disease, although this is not always the case.15Patients expe-
rience night-blindness and development of a progressive loss of
their visual field at ?10 years of age with severe visual impair-
ment before the age of 20, due to early macular involvement.13
RP12 with PPRPE can be heterogenous in its phenotype and is
seen most consistently in the equatorial and peripheral regions
of the eye. CRB1 mutations have been associated with the
development of Coats’-like exudative vasculopathy in patients
PCRA is a rare retinal disorder characterized by the pres-
ence of bilaterally symmetrical chorioretinal atrophy, with
From the1Ophthalmic Research Centre, Institute of Clinical Sci-
ence, Queen’s University of Belfast, Belfast, Northern Ireland, United
Kingdom; and the2Department of Biochemistry, University of Oxford,
Oxford, United Kingdom.
Supported by Neuroscience Grant RRG 11.14 from the R&D
Office, a directorate of the Northern Ireland Health and Social Services
Central Services Agency (DACS, GS).
Submitted for publication June 22, 2004; revised September 3,
2004; accepted September 22, 2004.
Disclosure: G.J. McKay, None; S. Clarke, None; J.A. Davis,
None; D.A.C. Simpson, None; G. Silvestri, None
The publication costs of this article were defrayed in part by page
charge payment. This article must therefore be marked “advertise-
ment” in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Corresponding author: David A. C. Simpson, Ophthalmic Re-
search Centre, Institute of Clinical Science, Queen’s University of
Belfast, Grosvenor Road, Belfast BT12 6BA, UK;
Investigative Ophthalmology & Visual Science, January 2005, Vol. 46, No. 1
Copyright © Association for Research in Vision and Ophthalmology
Previous studies have also described mutations in the CRB1
gene associated with Leber congenital amaurosis (LCA).13,15–19
LCA is considered the earliest and most severe form of retinal
dystrophy, causing blindness or severe visual impairment at
birth or during the early months of life. Onset of human
genetic retinal disease usually results in retinal thinning due to
progressive photoreceptor degeneration. However, a recent
investigation using optical coherence tomography reported
coarsely laminated retinal thickening,18lacking the distinct
layers of normal adult retina, in association with CRB1 muta-
tions in patients with LCA. In these cases the CRB1 mutant
retinal phenotype may present an immature lamination pattern
resulting from interrupted naturally occurring developmental
apoptosis. This is the first report of a mutation associated with
PPCRA, and we suggest possible structural effects on the CRB1
Full ophthalmic examination and fundus photography were performed
on seven family members and one spouse, the proband’s father (Fig.
1). The family and 150 control individuals were white. All patients gave
informed consent to participate in this study, which adhered to the
tenets of the Declaration of Helsinki and was approved by internal
institutional review (QUB 74/03). Electrophysiology was performed in
three of the second-generation individuals and optical coherence scan-
ning tomography (OCT) was performed on a subset of the family.
DNA was extracted from a blood sample provided under consent.
Sixteen amplicons spanning specific exons of several candidate genes
associated with retinal degeneration were analyzed (Table 1). In addi-
tion, 14 primer pairs (Table 2; Invitrogen Life Technologies, Paisley,
UK) were used to amplify all 12 exons of the CRB1 gene and their
flanking donor and acceptor splice sites, the 5? noncoding promoter
region and part of the 3? untranslated region. In 150 control individuals
only exon 2 of the CRB1 gene was amplified. Each amplicon was
generated by polymerase chain reaction (PCR; Platinum PCR Super-
Mix; Invitrogen-Life Technologies) after initial denaturation at 94°C for
1 minute and 30 cycles of 94°C, 10 seconds; 50°C, 10 seconds; and
72°C, 20 seconds; and one cycle of 72°C, 7 minutes. PCR amplicons
were column purified (Promega, Madison, WI) and subjected to DNA
sequence analysis by dye termination chemistry (Big Dye Sequencing;
Applied Biosystems, Warrington, UK). Homology modeling of the
fourth EGF-like calcium-binding domain of CRB1 was performed
(Swiss-Model, ver. 36.0003; http://www.expasy.org/spdbv/ provided
in the public domain by the Swiss Institute of Bioinformatics, Geneva,
A 28-year-old man (proband) was referred for evaluation of a
pigmentary retinopathy (Fig. 2). A diagnosis of PPCRA with
optic disc drusen was made. The patient reported no symp-
toms on presentation; however, he subsequently suffered a
serious decline in visual function over the next 3 years.
Clinical examination revealed that the proband’s father was
unaffected, but although his mother and two siblings were
asymptomatic, they showed clinical signs of early PPCRA. The
proband’s mother (II:2) was aged 62 at the time of examina-
tion. She showed moderate chorioretinal atrophy in the infe-
rior quadrant associated with paravenous pigmentary changes
in the far periphery. The woman, who was ill, was examined at
a CRB1 mutation in a family with
PPCRA. The letters below each ped-
igree number refer to the CRB1 se-
quence at position 619 of the cDNA.
All six affected members of the fam-
ily have the A allele, whereas the one
unaffected member (II:6) is homozy-
gous for G. The detailed phenotypes
of the proband (indicated with an
arrow) and other affected individu-
als are given in the text. The pro-
band’s father (II:1) was also exam-
ined to confirm that he had no retinal
degeneration. Current ages of indi-
viduals involved in the study are
shown above and to the right of the
Cosegregation analysis of
TABLE 1. Genes Partially DNA Sequenced in Addition to CRB1 in an
Initial Screening for the Detection of Mutations Associated
IOVS, January 2005, Vol. 46, No. 1
Mutation in CRBI Associated with PPCRA 323
home and is now deceased. It was therefore difficult to capture
the pigmentary changes in the far periphery with the handheld
camera. However, moderate chorioretinal atrophic changes in
the inferior quadrant were recorded (Figs. 3 A, 3B). Individual
II:5, a woman, was severely affected with very poor visual
acuity. Although the changes in this 59-year-old individual
were panfundoscopic, the more severe chorioretinal atrophy
and pigmentation were again located in the inferior quadrant
(Figs. 3C, 3D). Individual II:6, aged 56, was found to have no
evidence of any atrophy or pigmentation and was deemed
unaffected. Individual III:2, a 36-year-old woman, showed very
early chorioretinal atrophy in the inferior quadrant but, as yet
no pigmentary changes, and had normal electrophysiology.
Individual III:4 (a 27-year-old man) showed more obvious cho-
rioretinal atrophy inferiorly, with some very early pigmentary
changes (Fig. 4) and had subnormal rod ERGs in both eyes.
OCT scanning in this family indicated that retinal thickness
and lamination were within normal limits (Fig. 5A). An OCT
scan taken through an area of bony spicule pigmentation indi-
cated that the pigment lies in the superficial neuroretina (Figs.
A heterozygous c.619G3A single nucleotide variation in CRB1
(GenBank accession number AY043325) resulting in an amino
acid change from valine to methionine was detected at codon
162 within the fourth EGF-like domain. Of the seven family
members examined, the Val162Met variation was found to
cosegregate with six affected family members and was not
found in one unaffected family member (Fig. 1), giving a lod
score of 1.8. This nucleotide variation was not detected in 150
control individuals analyzed.
Homology modeling of the fourth EGF-like domain was per-
formed (Swiss-Model, ver. 36.0003; http://www.expasy.org/
spdbv/),20,21based on structural data for the calcium binding
EGF-like domains of coagulation factor VII, which has a high
degree of primary sequence identity (Fig. 6A). The Val162Met
variation is adjacent to the fourth highly conserved cysteine
and is a semiconservative substitution, with valine being re-
placed with the larger, nonaliphatic methionine residue. De-
duction of any structural effect is challenging because Val162 is
not conserved, but that amino acid residue is involved in
hydrogen bonding between the antiparallel ?-strands of the
TABLE 2. Primer Sequences and Product Size for Each Amplicon
AmpliconSense Primer Antisense Primer
An annealing temperature of 50°C was used for each amplicon. UTR, untranslated region.
* Taken from den Hollander.12
ical distribution of chorioretinal atrophy in the inferior quadrant (A)
associated with paravenous pigmentation (B).
Fundus photograph of the proband demonstrating the typ-
of individual II:2, age 62, showing moderate chorioretinal atrophy in
the inferior quadrant associated with paravenous pigmentary changes
in the far periphery (not shown). (B) Extensive chorioretinal atrophy
in the left eye of individual II:2 in the inferior periphery. (C) Right
posterior pole of individual II:5, showing advanced changes. (D) Right
nasal quadrant of individual II:5, showing advanced chorioretinal atro-
phy and pigmentary changes.
Fundus photography of patients with PPCRA. (A) Left eye
324 McKay et al.
IOVS, January 2005, Vol. 46, No. 1
major ?-sheet; in CRB1 the backbone amide/carbonyl of
Val162 hydrogen bonds with those of Phe173 (Fig. 6B). A
possibility is that changing the side-chain would result in suf-
ficient perturbation of the backbone that the domain-stabiliz-
ing hydrogen bond does not form or is weakened.
Subtle symmetrical chorioretinal atrophy in the inferior quad-
rant is the earliest clinical sign of PPCRA detectable within this
family. This geographic pattern correlates with the clinical
spotting of the inferior nasal quadrant of the fundus of rd8
mice, which have a point mutation in the Crb1 gene.22Para-
venous pigmentation occurs initially in the far periphery but,
as the disease progresses, moves more centrally with the cho-
rioretinal atrophy becoming more widespread, with involve-
ment of the nasal, then the temporal and finally the upper
quadrant. Both males and females have variable expressivity.
Males are more likely to exhibit a severe phenotype, whereas
females may remain virtually asymptomatic, even in later years.
The reason for the differential expression of the disease pro-
cess remains unexplained; however, it is consistent with a
mutation in CRB1,5,9,10,23in which mutations have been re-
ported to cause a wide spectrum of phenotypes.12–14,24The
specific CRB1 mutation reported affects the phenotype ob-
served, with loss of function more likely to result in LCA and
residual function associated with RP.24In addition, the same
mutations can lead to different phenotypes, with inconsistent
characteristics such as PPRPE and Coats’-like exudative vascu-
lopathy.13,14,24Therefore other genetic modifiers and environ-
mental factors may influence the effect of CRB1 mutations.
The earliest reported cases of PPCRA suggested an inflam-
matory cause because one affected individual was diagnosed
with tuberculous spondylitis,2a child with congenital syphi-
lis,25another with rubeola retinopathy,26and another with
ocular inflammation with cystoid macular edema.7In accor-
dance with the previous reports relating to the hereditary
etiology of this disease,3,5,9,23,27we found no evidence of an
inflammatory or infectious origin within this family. The auto-
somal dominant mode of inheritance observed in this family is
consistent with most of the information available from previ-
ous reports of PPCRA.9,10Our experience supports sugges-
tions that sporadic cases may in fact be revealed to be familial,
if asymptomatic relatives are examined.3,6
The CRB1 gene is composed of 12 exons and encodes a
transmembrane protein with 19 epidermal growth factor
(EGF)-like domains, three laminin A globular-like domains, and
a 37-amino-acid cytoplasmic tail. It is expressed in human
retina and brain, with evidence of alternative splicing at its 3?
end and is thought to encode four different isoforms, two of
which are found in human retina.28Crumbs, the Drosophila
orthologue of CRB1, forms part of one of the many protein
complexes along the plasma membrane that participate in
cell-to-cell contact and has been shown to be a key regulator of
epithelial apical–basal polarity.29The function of the intracel-
lular domain of Crumbs and CRB1 in localizing the phototrans-
duction complex to the apical membranes of photoreceptors
appears to be conserved from Drosophila to humans.28,30,31
The extracellular domain of Crumbs is essential to suppress
light-induced photoreceptor degeneration.32In mice, Crb1,
the murine orthologue of CRB1 is located apical to the zonula
adherens in photoreceptors and is necessary for the integrity of
the external limiting membrane.22,33A report of abnormal
lamination and increased retinal thickness in patients with
certain CRB1 mutations18suggests a role in laminar develop-
ment. This function does not appear to be affected by the
Val162Met mutation, because retinal thicknesses measured by
OCT were within the normal range.
All the CRB1 mutations previously reported to be associated
with retinal degeneration in humans have also been localized
to the extracellular portion of the protein, leading to amino
acid substitutions, frame shifts, or premature stop codons
(with the exception of one documented mutation at codon
1354 within the transmembrane domain, reported in an indi-
vidual with RP with Coats’-like exudative vasculopathy, in
conjunction with two additional mutations found within the
extracellular domain).12–16Among these mutations, Cys948Tyr
is the most common, having been associated with LCA, RP, RP
with Coats’-like exudative vasculopathy and RP with PPRPE. A
family has been reported in which affected individuals homozy-
gous for the Cys948Tyr mutation experience a severe LCA
phenotype.14This observation is in contrast to a compound
heterozygous family member with the Cys948Tyr mutation and
a nonsynonymous Ile1100Thr mutation, also within the CRB1
gene, resulting in an early onset RP phenotype without PPRPE.
It was concluded that the homozygous mutation results in a
complete loss of function of the CRB1 gene, whereas heterozy-
gosity is still likely to result in partial function. den Hollander et
al.12concurred with these findings, reporting homozygous
Cys948Tyr to be a severe mutation likely to lead to LCA. When
found heterozygously in combination with a splice-site muta-
tion that was unlikely to completely inactivate the protein, the
less severe RP with PPRPE resulted. Cys948Tyr occurs in what
appears to be a truncated EGF-like domain (the 14th EGF-like
domain). Although no high-resolution structural data are avail-
able, the amino acid sequence up to the fourth cysteine con-
forms to the EGF consensus sequence. In the typical EGF
structure, this cysteine forms a disulfide bond with the second
highly conserved cysteine (Cys933), and a nonsynonymous
substitution would therefore be expected to disrupt the native
fold of the domain.
The Val162Met mutation within CRB1 occurs in the fourth
EGF-like domain. EGF-like domains are widely distributed in
nature and are independently folding modules found in many
transmembrane and extracellular proteins.34Sequence similar-
ity among EGF-like domains is low at approximately 30%, they
are defined largely on the basis of the spacing between the
cysteines,35and they typically consist of six cysteine residues
that form disulfide bonds in a 1-3, 2-4, 5-6 arrangement. A
subset of EGF-like domains contains a consensus associated
showing normal posterior pole. (B) Right inferior quadrant showing
early chorioretinal atrophy. (C) Right inferior quadrant: midperiphery
showing moderate chorioretinal atrophy. (D) Right nasal quadrant
showing moderate chorioretinal atrophy.
Fundus photographs of individual III:4. (A) Right fundus
IOVS, January 2005, Vol. 46, No. 1
Mutation in CRBI Associated with PPCRA 325
with calcium binding. The residues that define this consensus
comprise those that directly bind the calcium atom (through
both side chain and backbone carbonyl H-bonding), those
involved in interdomain packing interactions, and those for
which clear functions have not yet been determined.36The
main structural feature of all EGF-like domains (both calcium-
binding and non–calcium-binding) is a central two-stranded
?-sheet that is located in the region of the sequence containing
the 1-3 and 2-4 disulfide bonds. The region separated by the 5-6
disulfide bond forms a ?-strand with hairpin turns at either end.
The 19 EGF domains comprise ?50% of CRB1 but contain
?70% of the nontruncating mutations, half of which directly
substitute one of the six signature cysteine amino acid residues
that disulfide bond to stabilize the global fold of the domain.
Other mutations introduce cysteine residues that could incor-
rectly form disulfide bonds. The remaining mutations have no
clear structural effect, and could mediate their disease-causing
phenotype through disruption of intradomain, interdomain, or
Human fibrillin-1 is a gene composed of similar calcium-
binding EGF domains and demonstrates similar mutation fre-
quency ratios within the EGF-like domains, emphasizing the
functional importance of these domains.37,38A relatively con-
servative Val1128Ile mutation similar to CRB1 Val162Met oc-
curs at the corresponding domain location within a calcium-
binding EGF-like domain of fibrillin 1 and is associated with
Marfan syndrome.39A variant of Marfan syndrome is also
caused by a conservative mutation at G1127S,40corresponding
to codon 161 within CRB1, a site previously reported to be
associated with RP through a conservative alanine-to-valine
substitution.12Both mutations within each gene have been
associated with disease, and all mutations are nominally con-
servative, although each substituted residue is larger than its
native counterpart. Smallridge et al.37reports that the G1127S
is likely to impair folding of the calcium-binding EGF-like do-
main, possibly because of the exchange of the glycine for a less
flexible residue at the start of the major ?-hairpin.
The mechanisms whereby mutations in CRB1 cause retinal
degeneration are unclear. Crb1 is required for maintenance of
the adherens junctions between photoreceptor and Mu ¨ller glia
cells.33Complete loss of Crb1 results in retinal disorganization
and dystrophy in mice, and null mutations in CRB1 result in
OCT scan of right macular area, fixa-
tion slightly eccentric showing nor-
mal thickness and lamination of the
retina. (B) OCT image of the left eye
showing a section through an area of
pigment in the neurosensory retina
(✱). (C) An area of blocked transmis-
sion at the location of pigment that is
in the intranasal quadrant (✱).
OCT of PPCRA retina. (A)
326 McKay et al.
IOVS, January 2005, Vol. 46, No. 1
LCA in humans.14EGF-like domains mediate protein interac-
tions, and the severity of the phenotype associated with mu-
tations within them presumably reflects the importance of the
specific interactions affected. Although previously reported
mutations within CRB1 are recessive, dominant mutations
within EGF-like domains of other proteins have been reported
to cause retinal disease, for example EFEMP1 Arg345Trp (dom-
inant drusen)41and HEMICENTIN-1 Gln5345Arg (ARMD1 phe-
notype).42It has been proposed that mutations within the
calcium-binding EGF-like domains of fibrillin-1 exert a domi-
nant negative effect by disrupting the function of the multi-
component 10- to 12-nm microfibrils of which fibrillin-1 is a
major constituent.43It is possible that the fourth CRB1 EGF-like
calcium-binding domain is involved in the assembly of an
extracellular scaffold structure and that the Val162Met muta-
tion disrupts the organization of this network. Further investi-
gation is necessary to confirm whether the mutational effect is
local to the domain or is implicated in a potential site of
protein–protein interaction. However, the extensive variation
in phenotypic presentation within this family suggests that
multiple interactions are likely to be involved.
The authors thank the family involved in this investigation for their
patience and cooperation and Gerry Mahon, Justin O’Neill, Vittorio
Silvestri, Anne Hughes, and Ronald Hunter for assistance with the
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of the major ?-sheet. Yellow: disul-
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chains and hydrogen bonds have
(A) Homology modeling
IOVS, January 2005, Vol. 46, No. 1
Mutation in CRBI Associated with PPCRA 327
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