The CRB1 gene is expressed in the retina and iris, where it is responsible for the apicobasal polarity of the neuroepithelium and later, the photoreceptor cell. The CRB1 gene has alternative splicing; the alternative splice variants encode either a 1,376-amino acid extracellular protein, or a 1,406-aa transmembrane protein with a 37-amino acid cytoplasmic domain. Both proteins consist of five different types of protein domains; a signal peptide, 19 EGF-like domains, and three laminin A G-like domains.
Defects in the CRB1 protein are associated with a severe form of retinitis pigmentosa, RP12, and with Leber Congenital Amaurosis 8.
The CRB1 gene maps to chromosome 1q31.3, and contains 12 coding exons, encompassing 276.9 kb of genomic DNA. Mutations in this gene have been reported in patients with a variety of autosomal recessive retinal dystrophies, including retinitis pigmentosa (RP) with preserved paraarteriolar retinal pigment epithelium (PPRPE), RP with Coats-like exudative vasculopathy, early onset RP without PPRPE, and Leber congenital amaurosis (LCA8). Mutations in the CRB1 gene are the cause of 10-15% LCA cases.
[See: Palestine > Beryozkin et al., 2013].
Gerber et al. (2002) identified a large consanguineous Arab family of Palestinian origin with multiple members affected with LCA. A genome wide screen for homozygosity showed no linkage to any of the then known six LCA genes, but showed linkage to a region on chromosome 1q, which carried the CRB1 gene. A 10-bd deletion mutation in exon 12 was found to segregate with the disease in this family. The mutation disrupted an amino acid sequence that was shown to be crucial for the proper functioning of the protein.
Beryozkin et al. (2013) recruited over 400 families with autosomal recessive non-syndromic retinal degenerations. SNP array analysis was performed on 175 index cases, eight of whom carried a homozygous region on chromosome 1 harboring CRB1. A subsequent CRB1 mutation analysis of the eight families, followed by screening of candidate founder mutations in the whole cohort of patients, revealed a total of 13 mutations, six of which are novel, in 15 families. Nine mutations were family-specific, and four were founder mutations identified in patients of Arab-Muslim origin, and Jews originating from Iraq and Kurdistan. A null mutation on at least one of the two mutated CRB1 alleles results in the LCA diagnosis, whereas patients carrying missense mutations were diagnosed with either RP or LCA. The average age at which CRB1 patients were referred to ERG testing was young (11 years). Of the 30 identified CRB1 patients, five had Coats-like exudative vasculopathy.
In 37 Saudi consanguineous families with Leber congenital amaurosis, Li et al. (2009) performed direct PCR and sequencing for 13 known LCA genes (GUCY2D, CRX, RPE65, TULP1, AIPL1, CRB1, RPGRIP1, LRAT, RDH12, IMPDH1, CEP290, RD3, LCA5). Of 417 individuals from these families, 117 were affected. A homozygous p.W93X mutation in the CRB1 gene was identified in two affected patients from the same family.
Aldahmesh et al. (2009) studied 52 Retinitis Pigmentosa (RP) affected individuals from 17 Saudi families to determine their underlying genetic defects. DNA obtained from the patients was used to carry out linkage analysis and homozygosity mapping studies. Regions of homozygosity were screened for known RP genes which were then analyzed for mutations. This revealed two novel CRB1 mutations: a homozygous c. 3159T>G mutation resulting in a p.C1053W substitution affecting four members of a family, and a homozygous c.80G>C mutation resulting in a p.C27F substitution affecting one individual. Both missense mutations were found to affect highly conserved residues and neither of the mutations were found in 100 ethnically matched controls.
Monies et al. (2017) outlined the genomic landscape of Saudi Arabia based on the findings of 1000 diagnostic panels and exomes. One patient, a 13-year-old female, suffered from microcephaly, fine/gross motor delay, speech delay, intellectual disability, learning disability, autistic features, ataxia, high blindness and retinitis pigmentosa. Whole exome sequencing helped identify a dual molecular diagnosis in this patient. A homozygous mutation (c.1898C>T, p.T633M) was found in exon 5 of the patient’s CRB1 gene, associated with retinitis pigmentosa 12, and a homozygous variant (c.346C>A, p.P116T) was uncovered in exon 4 of the ADIPOR1 gene, associated with intellectual disability (ID). Such dual molecular diagnoses were rare and only occurred in 1.5% of the cohort. Further, as the ADIPOR1 gene had previously been tentatively linked to ID, this report helped confirm its association with the disorder.
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