Alternative titles; symbols
HGNC Approved Gene Symbol: CRB1
SNOMEDCT: 723450004;
Cytogenetic location: 1q31.3 Genomic coordinates (GRCh38) : 1:197,201,504-197,478,455 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1q31.3 | Leber congenital amaurosis 8 | 613835 | Autosomal recessive | 3 |
| Pigmented paravenous chorioretinal atrophy | 172870 | Autosomal dominant | 3 | |
| Retinitis pigmentosa-12 | 600105 | Autosomal recessive | 3 |
To isolate candidate genes for chorioretinal diseases, den Hollander et al. (1999) cloned cDNAs specifically or preferentially expressed in the human retina and the retinal pigment epithelium (RPE) through a novel suppression subtractive hybridization (SSH) method (Diatchenko et al., 1996). One of these cDNAs (RET3C11) mapped to 1q31-q32.1, a region harboring a gene involved in a severe form of autosomal recessive retinitis pigmentosa characterized by a typical preservation of the paraarteriolar RPE, designated RP12 (600105). Den Hollander et al. (1999) isolated the full-length cDNA, encoding an extracellular protein with 19 EGF-like domains, 3 laminin-A G-like domains, and a C-type lectin domain. This 1,376-amino acid protein, 35% identical to the protein 'crumbs' (CRB) of Drosophila melanogaster, was denoted CRB1 for crumbs homolog-1. The CRB1 gene consists of 11 exons and spans at least 40 kb. Northern blot analysis detected a 5-kb transcript in neural retina; RT-PCR detected expression additionally in adult and fetal brain. The similarity to Drosophila CRB suggested a role for CRB1 in cell-cell interaction and possibly in the maintenance of cell polarity in the retina.
Roh et al. (2002) obtained a full-length cDNA encoding CRB1. The protein contains a transmembrane segment and a 37-amino acid tail. It is associated in tight junctions with MPP5 (606958) and PATJ (603199).
The polarized architecture of epithelial cells depends on the highly stereotypic distribution of cellular junctions and other membrane-associated protein complexes. In epithelial cells of the Drosophila embryo, 3 distinct domains subdivide the lateral plasma membrane. The most apical one comprises the subapical complex. It is followed by the zonula adherens, and, further basally, by the septate junction. A core component of the subapical complex is the transmembrane protein crumbs, the cytoplasmic domain of which recruits the PDZ protein Patj (603199) into the complex. Cells lacking crumbs or the functionally related gene 'stardust' fail to organize a continuous zonular adherens and to maintain cell polarity. Bachmann et al. (2001) demonstrated that stardust provides an essential component of the subapical complex. Stardust proteins colocalize with crumbs and bind to the carboxy-terminal amino acids of its cytoplasmic tail.
Pellikka et al. (2002) showed that crumbs and CRB1 localize to corresponding subdomains of the photoreceptor apical plasma membrane: the stalk of the Drosophila photoreceptor and the inner segment of mammalian photoreceptors. The subdomains support the morphogenesis and orientation of the photosensitive membrane organelles: rhabdomeres and outer segments, respectively. Drosophila crumbs is required to maintain zonula adherens integrity during the rapid apical membrane expansion that builds the rhabdomere. Crumbs also regulates stalk development by stabilizing the membrane-associated spectrin cytoskeleton, a function mechanistically distinct from its role in epithelial apical-basal polarity. Pellikka et al. (2002) proposed that crumbs is a central component of a molecular scaffold that controls zonula adherens assembly and defines the stalk as an apical membrane subdomain.
Izaddoost et al. (2002) described the properties of crumbs that control the position and integrity of the photoreceptor adherens junction and photosensitive organ, or rhabdomere, in Drosophila. In contrast to normal photoreceptor adherens junctions and rhabdomeres, which span the depth of the retina, adherens junctions and rhabdomeres of crumbs-deficient photoreceptors initially accumulate at the top of the retina and fail to maintain their integrity as they stretch to the retinal floor. Izaddoost et al. (2002) showed that crumbs controls localization of the adherens junction through its intracellular domain containing a putative binding site for a protein 4.1 superfamily protein (FERM). Although loss of crumbs or overexpression of the FERM binding domain caused mislocalization of adherens junctions, they did not result in a significant loss of photoreceptor polarity. The intracellular domain of human CRB1 behaved similarly to its Drosophila counterpart when overexpressed in the fly eye.
A striking difference between CRB1 and crumbs is that the latter contains a transmembrane region and a 37-amino acid cytoplasmic domain. Den Hollander et al. (2001) described an alternative splice variant of human CRB1 that encodes a cytoplasmic domain 72% similar to that of Drosophila crumbs. Two intracellular subdomains that are necessary for function in Drosophila are absolutely conserved. Rescuing and overexpression studies in Drosophila showed that the cytoplasmic domains are functionally related between these distant species. The authors hypothesized that CRB1 may organize an intracellular protein scaffold in the human retina.
Jacobson et al. (2003) characterized the retinal organization in vivo of patients with CRB1 mutations and found that, unlike other inherited retinal degenerations, the CRB1 mutant retinas were remarkably thick in cross-section and lacked the distinct layers of normal adult retina. There were coarse outer and inner zones and a thick surface layer around the optic nerve. The abnormal retinal architecture in CRB1 mutations resembled that of immature normal retina. Jacobson et al. (2003) concluded that the CRB1 disease pathway disturbs the development of normal human retinal organization by interrupting naturally occurring apoptosis.
Den Hollander et al. (2004) stated that 71 different sequence variants had been identified in the CRB1 gene in patients with retinal dystrophies. They provided an overview of currently known CRB1 variants and discussed their effects.
Henderson et al. (2011) sought to identify CRB1 mutations in a large cohort of patients with recessive retinal dystrophies and to document the retinal phenotype and visual prognosis. They recruited 306 patients with Leber congenital amaurosis (LCA), early-onset childhood retinal dystrophy, or juvenile-onset retinitis pigmentosa to the study. Mutations in CRB1, including 17 novel mutations, were identified in 41 patients from 32 families, and those patients underwent detailed phenotyping. Common phenotypic features included hypermetropic refractive error, nummular pigmentation at the level of the retinal pigment epithelium (RPE), and increased retinal thickness on optical coherence tomography (OCT). Most patients had a clinical and electrophysiologic phenotype consistent with a diagnosis of LCA or rod-cone dystrophy, but 3 patients had electroretinogram evidence of cone-rod degeneration. A minority of patients developed peripheral retinal telangiectasia, which in some cases led to seclusio pupillae and angle-closure glaucoma. Henderson et al. (2011) concluded that mutations in CRB1 were associated with a range of recessively inherited retinal dystrophies, including LCA and childhood- and juvenile-onset rod-cone and cone-rod dystrophy. Although the phenotype was usually severe, in milder cases there was a window of opportunity for therapeutic intervention in early childhood.
Bujakowska et al. (2012) analyzed the CRB1 gene in 400 index patients with a provisional diagnosis of retinitis pigmentosa and identified 11 patients carrying likely pathogenic variants of CRB1. Analysis of the more than 150 previously reported CRB1 mutations and the clinical features of the respective patients showed that no specific allele combination could be assigned to a particular phenotype. Bujakowska et al. (2012) suggested that the modulation of phenotype in patients with CRB1 mutations is due to additional modifying factors, genetic and/or environmental.
Retinitis Pigmentosa 12
In 10 unrelated RP12 (600105) patients, den Hollander et al. (1999) identified a homozygous AluY insertion disrupting the open reading frame, 5 homozygous missense mutations, and 4 compound heterozygous mutations in the CRB1 gene. The distinct RPE abnormalities observed in RP12 patients suggested that CRB1 mutations trigger a novel mechanism of photoreceptor degeneration.
Den Hollander et al. (2001) identified CRB1 mutations in 5 of 9 patients who had RP with Coats-like exudative vasculopathy, a relatively rare complication of RP that may progress to partial or total retinal detachment. Given that 4 of 5 patients had developed the complication in one eye and that not all sibs with RP have the complication, den Hollander et al. (2001) suggested that CRB1 mutations should be considered an important risk factor for the Coats-like reaction, although its development may require additional genetic or environmental factors.
In affected members of a consanguineous family with early-onset retinitis pigmentosa, Benayoun et al. (2009) identified compound heterozygosity for a G1103R mutation (604210.0011) and a 10-bp deletion (604210.0012) in the CRB1 gene. Each mutation had previously been identified in homozygosity in a family diagnosed with Leber congenital amaurosis (LCA8; 613835).
Leber Congenital Amaurosis 8
Lotery et al. (2001) screened the candidate gene CRB1 in 190 patients with Leber congenital amaurosis (LCA8; 613835) who were negative for mutation in 6 known LCA genes and 140 controls, and identified 21 patients and 2 controls who harbored amino acid-altering sequence variants (p = 0.03; see, e.g., 604210.0013). The authors noted that the 21 CRB1 mutation-carrying patients represented 9% of their total cohort of 233 LCA patients, making CRB1 the most commonly mutated gene in this group of patients.
Because of the early onset of disease in patients who have retinal pigmentosa with preserved paraarteriolar retinal pigment epithelium (RP12), with severe loss of vision at ages of less than 20 years, den Hollander et al. (2001) considered CRB1 to be a good candidate gene for Leber congenital amaurosis. They detected mutations in CRB1 in 7 (13%) of 52 patients with LCA from the Netherlands, Germany, and the United States (see, e.g., 604210.0006-604210.0007). Although no clear-cut genotype-phenotype correlation could be established, den Hollander et al. (2001) found that patients with LCA, which is the most severe retinal dystrophy, carried null alleles more frequently than did patients with retinitis pigmentosa.
In all 4 affected members of a Middle Eastern family with LCA8 and high to extreme hyperopia, Abouzeid et al. (2006) found linkage of the disorder to 1q31 and identified homozygosity for a mutation in the CRB1 gene (G1103R; 604210.0011). Abouzeid et al. (2006) showed that hyperopia and LCA were linked to the mutant CRB1 gene itself and were not dependent on unlinked modifiers.
Pigmented Paravenous Chorioretinal Atrophy
In all 6 affected members of a family segregating pigmented paravenous chorioretinal atrophy (PPCRA; 172870), McKay et al. (2005) identified heterozygosity for a val162-to-met (V162M; 604210.0010) mutation.
Mehalow et al. (2003) identified a mouse model, retinal degeneration-8 (rd8), with a single base deletion in the Crb1 gene. The mutation was predicted to cause a frameshift and premature stop codon with loss of the transmembrane and cytoplasmic domains of CRB1. Similar to Drosophila crumbs (crb) mutants, staining for adherens junction proteins was discontinuous and fragmented. Shortened photoreceptor inner and outer segments were observed as early as 2 weeks after birth, suggesting a developmental defect in these structures rather than a degenerative process. Photoreceptor degeneration was observed only within regions of retinal spotting. Since photoreceptor dysplasia and degeneration in Crb1 mouse mutants strongly varied with genetic background, the authors suggested that the variable phenotypes of human patients with CRB1 mutations may be due to interactions with background modifiers in addition to allelic variations.
In a patient with retinitis pigmentosa with paraarteriolar preservation of retinal pigment epithelium (RP12; 600105), den Hollander et al. (1999) found a homozygous insertion of an Alu repeat DNA element in exon 7 at nucleotide 2320 of the CRB1 cDNA. The Alu element belonged to the AluY subfamily, was oriented in the antisense direction, contained a more than 70-nucleotide poly(A) tail, and was flanked by a 12-bp direct repeat consisting of CRB1 nucleotides 2309-2320. This insertion was present in heterozygous state in the unrelated parents and in 2 sibs of the patient, but not in 185 healthy controls. The Alu sequence showed a 5-prime truncation that was also observed in a pathologic Alu element inserted in the F9 gene of hemophilia B (Vidaud et al., 1993); see 300746.0098.
In a patient with retinitis pigmentosa-12 (RP12; 600105), den Hollander et al. (1999) observed a homozygous nonconservative met1041-to-thr (M1041T) mutation in the CRB1 gene. This patient was from the family described by Bleeker-Wagemakers et al. (1992) in which the RP12 locus was originally mapped. The same mutation was found in heterozygosity in 1 of 100 healthy control individuals living in the same region as the patient.
In a patient with retinitis pigmentosa-12 (RP12; 600105), den Hollander et al. (1999) found a glu995-to-ter (E995X) mutation due to a 3118G-T transversion in the CRB1 gene and present in compound heterozygous state with an arg764-to-cys (R764C; 604210.0004) mutation on the other allele.
For discussion of the arg764-to-cys (R764C) mutation in the CRB1 gene that was found in compound heterozygous state in a patient with retinitis pigmentosa-12 (RP12; 600105) by den Hollander et al. (1999), see 604210.0003. The R764C mutation was also observed in compound heterozygous state with a ser430-to-ter (S430X) nonsense mutation.
In a patient with retinitis pigmentosa-12 (RP12; 600105), den Hollander et al. (1999) observed homozygosity for a thr745-to-met (T745M) mutation due to a 2369C-T transition in the CRB1 gene. The same T745M mutation was present in compound heterozygous state with another missense mutation in 1 patient.
In 2 brothers with Leber congenital amaurosis-8 (LCA8; 613835), den Hollander et al. (2001) found compound heterozygosity for a missense mutation (ile1100 to arg; I1100R) and a glu1333-to-ter mutation (E1333X; 604210.0007) in the CRB1 gene.
For discussion of the glu1333-to-ter (E1333X) mutation in the CRB1 gene that was found in compound heterozygous state in brothers with Leber congenital amaurosis-8 (LCA8; 613835) by den Hollander et al. (2001), see 604210.0006.
In a brother and sister with retinitis pigmentosa (RP12; 600105) who developed a Coats-like exudative vasculopathy (see 300216), den Hollander et al. (2001) found compound heterozygosity for a nonsense mutation, lys801 to ter (K801X), and a missense mutation, cys1181 to arg (C1181R; 604210.0009), in the CRB1 gene.
For discussion of the cys1181-to-arg (C1181R) mutation in the CRB1 gene that was found in compound heterozygous state in sibs with retinitis pigmentosa-12 (RP12; 600105) by den Hollander et al. (2001), see 604210.0008.
In all 6 affected members of a family with pigmented paravenous chorioretinal atrophy (PPCRA; 172870), McKay et al. (2005) identified heterozygosity for a val162-to-met (V162M) mutation within the fourth EGF-like domain of the CRB1 gene. PPCRA in this family was dominantly inherited but exhibited variable expressivity.
In all 4 affected members of a family of Middle Eastern origin segregating autosomal recessive Leber congenital amaurosis-8 (LCA8; 613835) and high to extreme hyperopia, Abouzeid et al. (2006) identified homozygosity for a 3307G-A transition in exon 9 of the CRB1 gene, resulting in a gly1103-to-arg (G1103R) substitution at a highly conserved site in the protein. The mutation was found in heterozygous state in 4 unaffected family members and was not found in 104 healthy Caucasian volunteers. Abouzeid et al. (2006) showed that hyperopia and LCA were linked to the mutant CRB1 gene itself and were not dependent on unlinked modifiers. Abouzeid et al. (2006) noted that the G1103R mutation had previously been identified in compound heterozygous state in a patient with sporadic LCA by Hanein et al. (2004).
In affected members of a consanguineous family with early-onset retinitis pigmentosa (RP12; 600105), Benayoun et al. (2009) identified compound heterozygosity for the G1103R mutation and a 10-bp deletion (604210.0012) in the CRB1 gene.
In 4 affected sibs from a consanguineous family with early-onset retinitis pigmentosa (RP12; 600105), Benayoun et al. (2009) identified compound heterozygosity for the G1103R mutation (604210.0011) in exon 9 and a 10-bp deletion (4121del10) in exon 12 of the CRB1 gene. Four unaffected sibs carried only 1 mutant allele; 1 carrier of the 10-bp deletion was found among 139 control samples screened, indicating a carrier rate of 0.72% in this population. Benayoun et al. (2009) noted that both mutations had previously been identified in homozygosity in families with Leber congenital amaurosis (LCA8; 613835) (see Gerber et al., 2002 and 604210.0011, respectively).
In 7 patients with Leber congenital amaurosis (LCA8; 613835), Lotery et al. (2001) identified a G-A transition in the CRB1 gene that resulted in a cys948-to-tyr (C948Y) substitution. The mutation was present in homozygosity in 1 patient, in compound heterozygosity with a missense and a frameshift mutation in 2 patients, respectively, and in heterozygosity in 4 patients. The mutation was not found in 280 control alleles. Lotery et al. (2001) noted that C948Y had previously been reported in patients with retinitis pigmentosa (RP12; 600105) by den Hollander et al. (1999).
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