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Mutations in the CRB1 Gene Cause Leber Congenital Amaurosis
Andrew J. Lotery, MD, FRCOphth;
Samuel G. Jacobson, MD, PhD;
Gerald A. Fishman, MD;
Richard G. Weleber, MD;
Anne B. Fulton, MD;
P. Namperumalsamy, MD;
Elise Héon, MD;
Alex V. Levin, MD;
Sandeep Grover, MD;
Justin R. Rosenow, BS;
Kelly K. Kopp, BS;
Val C. Sheffield, MD, PhD;
Edwin M. Stone, MD, PhD
Arch Ophthalmol. 2001;119:415-420.
ABSTRACT
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Objectives To test the hypothesis that mutations in the CRB1 gene cause Leber congenital amaurosis (LCA) and, if so, to describe
the ocular phenotype of patients with LCA who harbor CRB1 sequence variations.
Patients One hundred ninety probands with a clinical diagnosis of LCA were selected
from a cohort of 233 probands ascertained in 5 different countries. The remaining
43 probands (18%) were excluded because they harbored sequence variations
in previously identified LCA genes.
Methods One hundred ninety unrelated individuals with LCA were screened for
coding sequence mutations in the CRB1 gene with single-strand
conformation polymorphism analysis followed by automated DNA sequencing.
Results Twenty-one of the 190 probands (9% of the total cohort of 233) and 2
(1.4%) of 140 controls harbored amino acid–altering sequence variations
in the CRB1 gene (P = .003).
Conclusions In our cohort of patients with LCA, coding sequence variations were
observed in the CRB1 gene more frequently than in
any of the other 5 known LCA-associated genes. Likely disease-causing sequence
variations have now been identified in 64 (28%) of 233 subjects in this cohort.
Clinical Relevance Molecular diagnosis can confirm and clarify the diagnosis in an increasing
fraction of patients with LCA. As genotype data accumulate, clinical phenotypes
associated with specific mutations may be established. This will facilitate
the counseling of patients regarding their visual prognosis and the likelihood
of associated systemic anomalies.
INTRODUCTION
LEBER CONGENITAL amaurosis (LCA) is a term used to refer to a group
of inherited retinal disorders characterized by severe, bilateral visual impairment
in infancy. The pupillary responses are sluggish, nystagmus is frequently
present, and the electroretinographic responses are markedly attenuated. The
eyes of affected children appear grossly normal, with clear media, pink optic
discs, and completely attached retinas. The fundus can initially appear normal,
although many patients exhibit a degree of vascular attenuation when first
examined. Pigmentary abnormalities, ranging from white dots to nummular dark
pigment clumps and even bone spicule–like changes, can be seen in some
patients. Coloboma-like lesions in the macula are a less common finding. High
refractive errors are sometimes present, and older patients may develop keratoconus,
presumably from the chronic trauma of the oculodigital reflex. Systemic disorders,
most often neurological, are observed in a small number of individuals. The
visual outcome can vary widely. Some children with LCA maintain measurable
acuity for decades, while others are completely and permanently blind in infancy.1-3
These disparate clinical findings are in part owing to the genetic heterogeneity
of this disorder. To date, mutations in 5 genes have been reported to cause
a subset of LCA. These include GUCY2D, encoding retinal
guanylate cyclase4; RPE65, encoding a retinal pigment epithelium–specific 65 KD5-6; CRX, encoding
the cone-rod homeobox-containing gene7; TULP1, encoding the Tubby-like protein 18;
and AIPL1, encoding aryl-hydrocarbon interacting
protein–like 1.9 The discovery of these
genes has stimulated the search for novel therapies for this currently untreatable
disease.10
The fraction of LCA resulting from these 5 genes varies widely. TULP1 has been associated with the LCA phenotype in only
a single family from the Dominican Republic.8
The contribution of the other genes to the worldwide prevalence of LCA has
been reported to be CRX, 2.8%; GUCY2D, 6.3%; RPE65, 6.8%2;
and AILP1, 7%.11 Thus,
the molecular cause for most cases of LCA is still unknown.
Retinitis pigmentosa (RP) is a term used to refer to another clinically
and genetically heterogeneous group of retinal degenerations that are closely
related to LCA. In fact, the distinction between LCA and RP is largely based
on age of onset of the visual dysfunction. Patients whose conditions are diagnosed
when they are younger than 1 year are likely to be classified as having LCA,
while those older than 1 year who develop photoreceptor degeneration are more
likely to be diagnosed as having RP. The similarity of these conditions suggests
that genes known to cause RP might also cause some cases of LCA. Indeed, 3
of the known LCA-associated genes—RPE65, CRX, and TULP1—are each
known to cause some cases of RP.11-14
CRB1 is a recently discovered gene that is
responsible for a distinctive form of autosomal recessive RP referred to as
RP12.15 Clinically, RP12 exhibits the unusual
feature of preservation of the periarteriolar retinal pigment epithelium.
Some individuals affected with RP12 first experience visual loss in childhood
and some have hyperopic refractive errors.16
The purpose of this study was to determine whether mutations in CRB1 might cause LCA in some individuals.
SUBJECTS, MATERIALS, AND METHODS
Informed consent was obtained from all study patients or their legal
guardians. Two hundred thirty-three probands with LCA were ascertained from
the United States (146), Canada (43), India (41), Israel (3), and Switzerland
(1). Forty-three of these patients were known from a previous study2 to harbor a likely disease-causing sequence variation
in a previously described LCA gene. These patients were excluded from the
present study because the likelihood of finding additional disease-associated
mutations was judged to be too low to warrant further consumption of their
often irreplaceable DNA samples. The DNA was extracted from peripheral blood
using a previously described protocol.17 One
hundred ninety probands were screened for mutations in the coding sequence
of the CRB1 gene with single-strand conformation
polymorphism analysis. Ninety-four control subjects from Iowa and 46 control
subjects from India were screened in an identical fashion. The primer sequences
used for the single-strand conformation polymorphism screening have been previously
described15 with the exception that, for exon
2, we used the following primer sequences: forward, GCAGCACAAAGGTCACAAG and
reverse, TCCTGATGGCAAATACCTCC. The polymerase chain reaction (PCR) amplification
products were denatured for 3 minutes at 94°C and then electrophoresed
on 6% polyacrylamide, 5% glycerol gels at 25 W for approximately 3 hours.
The gels were then stained with silver nitrate.18-19
The PCR products from samples with aberrant electrophoretic patterns were
then sequenced bidirectionally with fluorescent dideoxynucleotides on an automated
DNA sequencer (ABI model 377; PE Applied Biosystems, Foster City, Calif).
Clinical records of 19 probands and 1 affected sibling with amino acid–changing
sequence variations in the CRB1 gene were available
for review, and the resulting phenotypic information was tabulated.
RESULTS
MOLECULAR RESULTS
Thirty instances of 20 different amino acid–altering sequence
variations were observed in this study (Table 1). Twenty-eight of these changes were found among 21 LCA
probands while, only 2 were observed in the heterozygous state in 2 control
individuals (P = .003). Six LCA probands were each
found to harbor 2 amino acid–altering changes (presumably on different
alleles). One proband was homozygous (for Cys948Tyr) and another was homozygous
for Cys480Gly. The other 4 probands were compound heterozygotes. Fifteen of
the probands exhibited 1 heterozygous amino acid–altering change (Table 1).
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Table 1. CRB1 Sequence Variations*
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A total of 5 synonymous codon changes were observed—each unique,
4 present in single LCA probands and 1 in an Indian control. These were significantly
more likely to be found in an LCA proband with a single amino acid–changing CRB1 variation (2/15) than in LCA probands without an amino
acid–altering CRB1change (2/169; P = .03) or in controls (1/140; P = .03).
Four different intronic single nucleotide polymorphisms (SNPs) were
found among the study participants (Table
1), but these were not significantly skewed toward LCA probands
or controls (either singly or as a group). The most common intronic SNP was
located 12 bases upstream from the start of exon 2 and was identically distributed
(thymine, 40%; adenine, 60%) among the alleles of LCA probands and control
individuals. A single instance of a 4–base pair deletion in intron 2
was observed in a single LCA proband.
The most common amino acid–changing variant that we observed in
the LCA cohort (Cys948Tyr) has been previously observed in patients with RP12.15 The other 17 amino acid–changing variants have
not been previously reported.
CLINICAL RESULTS
Clinical records were available for 18 of the LCA probands with amino
acid–altering sequence variations and 1 affected sibling (Table 2). Nystagmus was noted in 18 of 19 patients, with "roving
eye movements" recorded for the remaining patient. The visual acuity ranged
from 20/40 in 1 eye of 1 patient, to light perception, with a median of 20/250.
A refraction was recorded in 37 eyes of 19 patients, and the average spherical
equivalent was +4.9 diopters (D) (range, -10.00 to +9.00 D). Electroretinogram
(ERG) data were available for 12 patients. In all cases the full-field ERG
was markedly reduced, and in 7 of 12 patients it was nondetectable. Detailed
retinal notes were available for 14 patients. Nummular pigment clumps were
seen in 9 of 14 patients (Figure 1),
and white spots (Figure 1, Figure 2, and Figure 3) were specifically mentioned in the notes of 5 of 14 patients.
Large zones of retinal pigment epithelium atrophy were present in 1 patient
(Figure 4), and coloboma-like lesions
of the macula were present in 3 others (Figure
5 and Figure 6). Keratoconus
was present in 2 siblings, and periarteriolar preservation of the retinal
pigment epithelium was seen in a different pair of siblings.
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Table 2. Clinical Features*
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Figure 1. Midperipheral fundus of patient
13 at age 19 years. The visual acuity at this visit was counting fingers.
Small white spots are admixed with nummular pigment clumps at the level of
the retinal pigment epithelium.
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Figure 2. Midperiphery of patient 9 at age
10 years. The visual acuity at this visit was 20/200 OD. Numerous small white
spots are admixed with fairly typical bone spicule–like pigmentation.
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Figure 3. Posterior pole of patient 10 at
age 21 years. The visual acuity in this eye at this visit was 20/400 OS. The
disc appears healthy, but there is mild vascular attenuation. There are diffuse
fine white spots throughout the fundus. There is an oval area of retinal pigment
epithelium (RPE) pigment disruption centered on the fovea and a few clumps
of bone spicule–like intraretinal pigment as well. There is a circular
area of atrophy or hypoplasia of the RPE and choriocapillaris along the superotemporal
arcade at the margin of the photograph.
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Figure 4. Posterior pole of the right eye
of patient 12 at age 11 years. The visual acuity on that visit was 20/300.
The optic nerve head appears fairly normal, but the fovea is not well developed.
The most striking finding is a zonal atrophy or hypoplasia of the choriocapillaris
and retinal pigment epithelium temporally and inferiorly, which largely spares
the macula.
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Figure 5. Posterior pole of the right eye
of patient 4 at age 1 year. The visual acuity in this eye was 20/3700 (with
Teller acuity cards). The retinal vasculature is attenuated, and a large area
of atrophy or hypoplasia of the retinal pigment epithelium and choriocapillaris
is present in the macula. This finding has often been called a macular coloboma.
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Figure 6. Posterior pole of patient 7 at
age 61 years. The visual acuity at this visit was counting fingers. The optic
disc is obscured by an area of vitreous opacity. There is widespread pigment
disruption of the retinal pigment epithelium (RPE) in addition to some overlying
bone spicule–like changes in the retina. There is a circular area of
atrophy or hypoplasia of the RPE and choriocapillaris just temporal to the
normal location of the fovea.
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COMMENT
Leber congenital amaurosis is a severe, genetically heterogeneous, autosomal
recessive retinal dystrophy. Including CRB1, mutations
in 6 genes have now been shown to cause the LCA phenotype. In our complete
cohort of 233 LCA probands, amino acid–changing CRB1 variants were found in 21 (9%), making CRB1
the most commonly mutated gene in this group of patients. However, most patients
with LCA in our cohort do not harbor sequence variations in any of these 6
genes. This is in part because other LCA genes undoubtedly exist, and in part
because some mutations will be missed by PCR-based assays of the coding sequences
such as the ones employed in this study. Such assays will not detect deletions
involving the primer sites or mutations in the promoters. Indeed, even among
the 21 patients with amino acid–changing CRB1
variants in this study, we were unable to detect any CRB1 variations in 15 (36%) of the alleles. Further extensive investigation
of these 15 alleles is warranted to try to identify additional regions of
the gene that will be fruitful to reexamine in the entire cohort.
The distribution of the synonymous codon variants observed in this study
is interesting. Although one would not usually expect such changes to contribute
to an altered phenotype (because the predicted protein sequence is not changed),
the significant distribution among patients with LCA vs controls (as well
as among patients with LCA with CRB1 mutations vs
those without mutations) suggests that these alleles may also be disease causing,
perhaps by altering the stability or processing of the CRB1 messenger RNA. Functional assays will be necessary to support
this hypothesis. Evaluation of a common SNP found within intron 1 does not
show a disease association, which indicates that our mutation screening assay
is unlikely to be missing a common CRB1 mutation
that would account for a large portion of the as yet undetected mutant alleles.
The biochemical function of CRB1 is currently
unknown. Comparison of CRB1 with the homologous Drosophila melanogaster crumbs protein (CRB) suggests that
it may be involved in neuronal development of the retina.15
This hypothesis would be consistent with the early onset of retinal dysfunction
seen in the patients in this study. Although the number of patients with LCA
in whom we found CRB1 coding sequence variations
is small, we observed 2 fairly constant phenotypic features: the presence
of moderate to high hyperopia and the relatively early appearance of white
spots and nummular pigment clumps. The preservation of the periarteriolar
retinal pigment epithelium phenotype (characteristic of RP1215)
was seen in 2 of our patients. This is a good example of an increasingly common
situation in which an established, clinically based nomenclature system fails
to correspond neatly with molecular reality at the DNA level. There are now
numerous examples in the field of retinal degeneration research in which a
gene that is initially shown to cause disease in patients with one clinical
phenotype is later found to cause disease in patients with another—sometimes
quite different—phenotype. These include (1) the RDS gene, which was initially found to cause RP but was later discovered
to be associated with pattern dystrophy and other maculopathies20-22;
(2) rhodopsin and PDEB, which were initially associated
with RP but later found to be associated with stationary night blindness23-24; (3) CRX
and GUCY2D, which each cause LCA and cone-rod dystrophy4, 7, 25-26; and
(4) RPE65, which causes LCA and RP.5, 12
This lack of perfect correspondence between clinical and molecular nomenclature
systems is not a serious obstacle to accurate communication as long as one
makes it clear which system is being used in a specific situation. Both systems
serve a useful purpose. Infants with severely impaired vision, nystagmus,
no striking ophthalmoscopic abnormalities, hyperopia, and a nonrecordable
ERG will continue to be given the clinical diagnosis of LCA, and it remains
an important goal to ultimately identify all the genes that are capable of
causing this phenotype. In contrast, scientists studying the biological roles
of individual genes like CRB1 will continue to be
interested in identifying all the different phenotypes that can be caused
by variations in that particular gene. In the present study, the frame of
reference was the clinical diagnosis of LCA, and the clinically relevant finding
is that 9% of a carefully defined LCA cohort harbor mutations in the CRB1 gene.
Less than 5 years ago, no patients with LCA could be molecularly diagnosed.
With the addition of CRB1 to the panel of LCA genes,
we now have a greater than 25% chance of detecting a disease-causing mutation
in a new patient with LCA. Molecular diagnosis is important for providing
accurate counseling about recurrence risk to affected families, as well as
for the identification of specific molecular subsets of patients for future
studies of novel interventions.
AUTHOR INFORMATION
Accepted for publication January 5, 2001.
This study was supported in part by National Institutes of Health, Bethesda,
Md, grants EY10539 and EY05627; the Foundation Fighting Blindness, Hunt Valley,
Md; the Grousbeck Family Foundation, Stanford, Calif; the Carver Endowment
for Molecular Ophthalmology, Muscatine, Iowa; the Daniel Matzkin Research
Fund; the Grant Healthcare Foundation; and an unrestricted grant from Research
to Prevent Blindness Inc, New York, NY. Dr Lotery is a recipient of a Research
to Prevent Blindness Career Development Award.
The authors thank Creig Hoyt, MD; James Jan, MD; Byron Lam, MD; Ronald
Carr, MD; John Heckenlively, MD; William Scott, MD; Douglas Fredrick, MD;
Ehud Zamir, MD; Saul Merin, MD; Francis Munier, MD; Arlene Drack, MD; Terry
Schwartz, MD; Jean Bennett, MD; Alessandro Iannaccone, MD; Maria Musarella,
MD; and Benedetto Falsini, MD, for sharing their patients with us for this
study. The authors also thank Luan Streb, BA; Christine Taylor, BS; Heidi
Haines, MS; Louisa Affatigato, BS; and Gretel Beck, BA, for their excellent
technical assistance and Jessica Emmons, BA; Elaine De Castro, BS; and Leigh
Gardner, BA, for clinical coordination.
Corresponding author and reprints: Edwin M. Stone, MD, PhD, Department
of Ophthalmology and Visual Sciences, The University of Iowa College of Medicine,
200 Hawkins Dr, Iowa City, IA 52242 (e-mail: edwin-stone{at}uiowa.edu).
From the University of Iowa College of Medicine, Iowa City (Drs Lotery,
Sheffield, and Stone, Mr Rosenow, and Ms Kopp); the Scheie Eye Institute,
Philadelphia, Pa (Dr Jacobson); the University of Illinois Eye and Ear Infirmary,
Chicago (Drs Fishman and Grover); the Casey Eye Institute, Portland, Ore (Dr
Weleber); Children's Hospital, Boston, Mass (Dr Fulton); Aravind Eye Hospital,
Madurai, India (Dr Namperumalsamy); the Eye Research Institute of Canada (Dr
Héon), and The Hospital for Sick Children (Dr Levin), Toronto, Ontario.
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Distinct roles of Bazooka and Stardust in the specification of Drosophila photoreceptor membrane architecture
Hong et al.
Proc. Natl. Acad. Sci. USA 2003;100:12712-12717.
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CRB1 is essential for external limiting membrane integrity and photoreceptor morphogenesis in the mammalian retina
Mehalow et al.
Hum Mol Genet 2003;12:2179-2189.
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An unusual retinal vascular morphology in connection with a novel AIPL1 mutation in Leber's congenital amaurosis
Heegaard et al.
Br J Ophthalmol 2003;87:980-983.
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Study of the involvement of the RGR, CRPB1, and CRB1 genes in the pathogenesis of autosomal recessive retinitis pigmentosa
Bernal et al.
J. Med. Genet. 2003;40:e89-89.
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Evidence of autosomal dominant Leber congenital amaurosis (LCA) underlain by a CRX heterozygous null allele
Perrault et al.
J. Med. Genet. 2003;40:e90-90.
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Crumbs homolog 1 (CRB1) mutations result in a thick human retina with abnormal lamination
Jacobson et al.
Hum Mol Genet 2003;12:1073-1078.
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Progession of phenotype in Leber's congenital amaurosis with a mutation at the LCA5 locus
Mohamed et al.
Br J Ophthalmol 2003;87:473-475.
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Electroretinographic Abnormalities in Parents of Patients With Leber Congenital Amaurosis Who Have Heterozygous GUCY2D Mutations
Koenekoop et al.
Arch Ophthalmol 2002;120:1325-1330.
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Molecular genetics of Leber congenital amaurosis
Cremers et al.
Hum Mol Genet 2002;11:1169-1176.
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The Leber congenital amaurosis gene product AIPL1 is localized exclusively in rod photoreceptors of the adult human retina
van der Spuy et al.
Hum Mol Genet 2002;11:823-831.
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CRB1 has a cytoplasmic domain that is functionally conserved between human and Drosophila
den Hollander et al.
Hum Mol Genet 2001;10:2767-2773.
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Implications of Genetic Analysis in Leber Congenital Amaurosis
Gamm and Thliveris
Arch Ophthalmol 2001;119:426-427.
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