Alternative titles; symbols
HGNC Approved Gene Symbol: RLBP1
SNOMEDCT: 715562001, 715647007, 764939004;
Cytogenetic location: 15q26.1 Genomic coordinates (GRCh38): 15:89,209,869-89,221,579 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 15q26.1 | Bothnia retinal dystrophy | 607475 | Autosomal recessive | 3 |
| Fundus albipunctatus | 136880 | Autosomal dominant; Autosomal recessive | 3 | |
| Newfoundland rod-cone dystrophy | 607476 | 3 | ||
| Retinitis punctata albescens | 136880 | Autosomal dominant; Autosomal recessive | 3 |
Cellular retinaldehyde-binding protein (CRALBP) is a 36-kD water-soluble protein which is found only in retina and pineal gland and which carries 11-cis-retinaldehyde or 11-cis-retinal as physiologic ligands (Sparkes et al., 1992). Several of its properties suggested that it is involved in the visual process and, therefore, potentially with retinal diseases.
Crabb et al. (1988) cloned cDNAs for this protein from bovine and human retina and demonstrated 92% identity in amino acid sequence. The sequence was not related to any other known protein sequence. Both the bovine and the human proteins contain 360 residues.
Intres et al. (1994) isolated genomic clones spanning 29 kb and encompassing the human RLBP1 gene. The gene is composed of 8 exons and 7 introns with average lengths of 198 bp and 1.2 kb, respectively, and with conventional vertebrate splicing mechanisms. The first exon is entirely untranslated, and both exon 2 and exon 8 contain untranslated regions.
Using a human cDNA probe, Sparkes et al. (1992) mapped the RLBP1 gene to human 15q26 by study of somatic cell hybrids and by in situ hybridization. They localized the mouse gene to chromosome 7 by study of somatic cell hybrids.
By studies in a consanguineous pedigree segregating for a form of nonsyndromic autosomal recessive retinitis pigmentosa, Maw et al. (1997) found that affected sibs were homozygous by descent for a 4763G-A nucleotide substitution in the RLBP1 gene. This substitution was predicted to replace an arginine with glutamine at residue 150 (180090.0001). CRALBP is not expressed in photoreceptors but is abundant in the retinal pigment epithelium (RPE) and Muller cells of the neuroretina, where it carries 11-cis-retinol and 11-cis-retinaldehyde. When expressed in bacteria, recombinant CRALBP containing the R150Q substitution was less soluble than wildtype recombinant CRALBP. Mutant CRALBP was purified and found to lack the ability to bind 11-cis-retinaldehyde. These findings suggested that the autosomal recessive disorder in the pedigrees studied resulted from a lack of functional CRALBP, presumably leading to a disruption of retinal vitamin A metabolism. Katsanis et al. (2001) noted that the phenotype described by Maw et al. (1997) suggested fundus albipunctatus (FA) or retinitis punctata albescens (RPA) (136880), with 'white dots scattered over the whole fundus.' They found the R150Q mutation in a consanguineous Saudi Arabian kindred with a retinal dystrophy phenotype that fulfilled the criteria of FA in younger individuals and RPA in older patients.
Eichers et al. (2002) identified 6 Newfoundland pedigrees with a severe rod-cone dystrophy, which they designated NFRCD (607476), that had an ophthalmoscopic appearance similar to that of retinitis punctata albescens (136880), but with age at onset typically in the first decade of life and with rapid progression, leading to legal blindness by the second to fourth decades and to a further decrease in visual acuity (such that, by the fifth decade, the affected individual was, at best, only able to count fingers). Mutation screening identified 2 splice-junction mutations in the RLBP1 gene present in different combinations in the 6 NFRCD pedigrees as the likely cause of disease. In contrast to expected homozygosity due to a founder effect, each mutation was transmitted through 2 different haplotypes, suggesting that the Newfoundland population is more diverse genetically than previously postulated (Bear et al., 1988).
Saari et al. (2001) found that the photosensitivity of Rlbp1-null mice was normal, but rhodopsin regeneration, 11-cis-retinal production, and dark adaptation after illumination were delayed more than 10-fold. All-trans-retinyl esters accumulated during the delay, indicating that isomerization of all-trans- to 11-cis-retinol was impaired. No evidence of photoreceptor degeneration was observed in animals raised in cyclic light/dark condition for up to 1 year. Albino Rlbp1-null mice were protected from light damage relative to the wildtype. Saari et al. (2001) concluded that RLBP1 is an acceptor of 11-cis-retinol in the isomerization reaction of the visual cycle.
In a consanguineous sibship with 5 individuals affected with a nonsyndromic retinal dystrophy identified as retinitis pigmentosa, Maw et al. (1997) found homozygosity by descent for a 4763G-A nucleotide substitution in the RLBP1 gene. The substitution was predicted to cause an arg150-to-gln (R150Q) amino acid substitution. In this Indian family the parents were first cousins. Three affected sibs living at the same time of the study had onset of night blindness at 3 and 4 years of age, with progression to legal blindness by their late twenties. Fundus examination showed optic disc atrophy, narrowing of the vessels, macular degeneration, and small white dots scattered over the entire fundus; bony spicule pigmentation was not present.
Katsanis et al. (2001) studied 4 consanguineous kindreds diagnosed with fundus albipunctatus (136880) from Saudi Arabia. Given the substantial phenotypic variation and overlap between different flecked retinal dystrophies, they evaluated all known genes associated with such conditions by both genetic analysis and direct sequencing. In 1 kindred, they identified a homozygous R150Q alteration in RLBP1. Examination of several patients aged 3 to 20 years over a 9-year period presented no evidence of either retinitis pigmentosa or retinitis punctata albescens (RPA). In contrast, clinical examination of individuals with the same mutation in their fourth and fifth decade revealed signs consistent with RPA. The data suggested that the R150Q mutation in RLBP1 may result in RPA with slow progression. More importantly, younger individuals diagnosed with the milder disorder fundus albipunctatus thought to be stationary may evolve to a more devastating and progressive phenotype. Katsanis et al. (2001) remarked that the phenotype described by Maw et al. (1997) suggested either fundus albipunctatus or RPA, with 'white dots scattered over the whole fundus.' The older patients reported by Katsanis et al. (2001) had a clinical picture consistent with the patients described by Maw et al. (1997).
In cases of Newfoundland rod-cone dystrophy (607476), Eichers et al. (2002) found homozygosity for an IVS3+2T-C splice mutation in the RLBP1 gene, or compound heterozygosity of this splice site mutation with 324G-A (180090.0003).
One of the mutations in the RLBP1 gene found by Eichers et al. (2002) as the cause of Newfoundland rod-cone dystrophy (607476) was a 324G-A transition, present in either homozygous state or in compound heterozygous state with the IVS3+2T-C mutation (180090.0002). Two distinct haplotypes were associated with the 324G-A mutation and 2 haplotypes associated with the IVS3+2T-C mutation. The data suggested either that both mutations were introduced into Newfoundland through 2 independent mutational events on 2 different chromosomes or that each mutation is relatively old and has undergone haplotype divergence. The higher prevalence of the 324G-A mutation suggested that this might be the initial mutation introduced into the Newfoundland population, a hypothesis consistent with the presence of this mutation in 1 of 106 Newfoundland control chromosomes and in none of 112 non-Newfoundland control chromosomes. This same mutation was observed in compound heterozygous state with the M225K mutation (180090.0005) in a patient with retinitis punctata albescens (136880) by Morimura et al. (1999).
A homozygous missense mutation in exon 7 of the RLBP1 gene, 9096C-T, which causes an arg234-to-trp (R234W) amino acid substitution, was associated with both Bothnia retinal dystrophy (607475) (Burstedt et al. (1999, 2001); Granse et al., 2001) and retinitis punctata albescens (136880) (Morimura et al., 1999).
Morimura et al. (1999) observed a patient with retinitis punctata albescens (136880) who was compound heterozygous for 2 mutations in the RLBP1 gene: IVS3+2T-C (180090.0002) and a met225-to-lys (M225K) missense mutation in exon 6.
Bear, J. C., Nemec, T. F., Kennedy, J. C., Marshall, W. H., Power, A. A., Kolonel, V. M., Burke, G. B. Inbreeding in outport Newfoundland. Am. J. Med. Genet. 29: 649-660, 1988. [PubMed: 3377008] [Full Text: https://doi.org/10.1002/ajmg.1320290324]
Burstedt, M. S., Sandgren, O., Holmgren, G., Forsman-Semb, K. Bothnia dystrophy caused by mutations in the cellular retinaldehyde-binding protein gene (RLBP1) on chromosome 15q26. Invest. Ophthal. Vis. Sci. 40: 995-1000, 1999. [PubMed: 10102298]
Burstedt, M. S. I., Forsman-Semb, K., Golovleva, I., Janunger, T., Wachtmeister, L., Sandgren, O. Ocular phenotype of Bothnia dystrophy, an autosomal recessive retinitis pigmentosa associated with an R234W mutation in the RLBP1 gene. Arch Ophthal. 119: 260-267, 2001. [PubMed: 11176989]
Crabb, J. W., Goldflam, S., Harris, S. E., Saari, J. C. Cloning of the cDNAs encoding the cellular retinaldehyde-binding protein from bovine and human retina and comparison of the protein structures. J. Biol. Chem. 263: 18688-18692, 1988. [PubMed: 3198595]
Eichers, E. R., Green, J. S., Stockton, D. W., Jackman, C. S., Whelan, J., McNamara, J. A., Johnson, G. J., Lupski, J. R., Katsanis, N. Newfoundland rod-cone dystrophy, an early-onset retinal dystrophy, is caused by splice-junction mutations in RLBP1. Am. J. Hum. Genet. 70: 955-964, 2002. [PubMed: 11868161] [Full Text: https://doi.org/10.1086/339688]
Granse, L., Abrahamson, M., Ponjavic, V., Andreasson, S. Electrophysiological findings in two young patients with Bothnia dystrophy and a mutation in the RLBP1 gene. Ophthal. Genet. 22: 97-105, 2001. [PubMed: 11449319] [Full Text: https://doi.org/10.1076/opge.22.2.97.2231]
Intres, R., Goldflam, S., Cook, J. R., Crabb, J. W. Molecular cloning and structural analysis of the human gene encoding cellular retinaldehyde-binding protein. J. Biol. Chem. 269: 25411-25418, 1994. [PubMed: 7929238]
Katsanis, N., Shroyer, N. F., Lewis, R. A., Cavender, J. C., Al-Rajhi, A. A., Jabak, M., Lupski, J. R. Fundus albipunctatus and retinitis punctata albescens in a pedigree with an R150Q mutation in RLBP1. Clin. Genet. 59: 424-429, 2001. [PubMed: 11453974] [Full Text: https://doi.org/10.1034/j.1399-0004.2001.590607.x]
Maw, M. A., Kennedy, B., Knight, A., Bridges, R., Roth, K. E., Mani, E. J., Mukkadan, J. K., Nancarrow, D., Crabb, J. W., Denton, M. J. Mutation of the gene encoding cellular retinaldehyde-binding protein in autosomal recessive retinitis pigmentosa. Nature Genet. 17: 198-200, 1997. [PubMed: 9326942] [Full Text: https://doi.org/10.1038/ng1097-198]
Morimura, H., Berson, E. L., Dryja, T. P. Recessive mutations in the RLBP1 gene encoding cellular retinaldehyde-binding protein in a form of retinitis punctata albescens. Invest. Ophthal. Vis. Sci. 40: 1000-1004, 1999. [PubMed: 10102299]
Saari, J. C., Nawrot, M., Kennedy, B. N., Garwin, G. G., Hurley, J. B., Huang, J., Possin, D. E., Crabb, J. W. Visual cycle impairment in cellular retinaldehyde binding protein (CRALBP) knockout mice results in delayed dark adaptation. Neuron 29: 739-748, 2001. [PubMed: 11301032] [Full Text: https://doi.org/10.1016/s0896-6273(01)00248-3]
Sparkes, R. S., Heinzmann, C., Goldflam, S., Kojis, T., Saari, J. C., Mohandas, T., Klisak, I., Bateman, J. B., Crabb, J. W. Assignment of the gene (RLBP1) for cellular retinaldehyde-binding protein (CRALBP) to human chromosome 15q26 and mouse chromosome 7. Genomics 12: 58-62, 1992. [PubMed: 1733864] [Full Text: https://doi.org/10.1016/0888-7543(92)90406-i]