Alternative titles; symbols
HGNC Approved Gene Symbol: RCBTB1
Cytogenetic location: 13q14.2 Genomic coordinates (GRCh38) : 13:49,531,946-49,585,558 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 13q14.2 | Retinal dystrophy with or without extraocular anomalies | 617175 | Autosomal recessive | 3 |
RCBTB1 shares significant homology with CHC1L (RCBTB2; 603524), a RCC1 (179710)-like guanine exchange factor that regulates transcription through chromatin remodeling.
Mabuchi et al. (2001) assembled a high-resolution physical map spanning the critical region deleted in B-cell chronic lymphocytic leukemia (109543) on chromosome 13q14 and identified RCBTB1, which they called CLLD7. The deduced 531-amino acid protein has a calculated molecular mass of about 58 kD. RCBTB1 contains an N-terminal RCC1 domain and a C-terminal BTB (broad complex-tramtrack-bric-a-brac) domain. The RCC1 domain has 6 intradomain repeats of about 42 to 53 residues. RCBTB1 shares 67% identity with CHC1L. Northern blot analysis detected a 4-kb transcript in all normal tissues and tumor cell lines examined.
Using the C-terminal 64 amino acids of rat angiotensin II receptor-1A (AGTR1A; 106165) as bait in a yeast 2-hybrid screen of a mouse embryo cDNA library, Guo et al. (2004) cloned a partial cDNA encoding Rcbtb1, which they called Glp. Using this partial sequence as probe, they cloned full-length human GLP from a vascular smooth muscle cell (VSMC) cDNA library. Northern blot analysis detected ubiquitous expression, with highest levels in kidney, pancreas, and heart. Western blot analysis of rat VSMCs, rat immortalized renal proximal tubular cells (IRPTCs), and HEK293 cells detected endogenous GLP at an apparent molecular mass of 58 kD. Fluorescence-labeled GLP localized in small vacuoles in the cytoplasm and on the plasma membrane of transfected HEK293 cells, but not in the nucleus.
Coppieters et al. (2016) analyzed in-house whole-transcriptome expression array data, which showed ubiquitous expression of human RCBTB1 RNA. The authors stated that RCBTB1 expression in the thyroid had been observed in experiments involving the EMBL-EBI Expression Atlas, and that RCBTB1 had previously been found to be moderately expressed in the cochlea, saccule, utricle, and ampulla of the adult human inner ear (Schrauwen et al., 2016). Coppieters et al. (2016) performed targeted analysis of expression of RCBTB1 and Rcbtb1 mRNA in various human and mouse tissues and observed relatively high expression of RCBTB1 mRNA in human retina, with limited expression in the retinal pigment epithelium (RPE), and strong expression of Rcbtb1 mRNA in mouse retina, RPE, and ovary. Staining of mouse retinal sections revealed staining mainly in the inner retina with strong signals reaching up to the outer plexiform layer, whereas in human sections, immunostaining was present in the nerve fiber layer and, to a lesser extent, in the inner and outer plexiform layers.
Mabuchi et al. (2001) determined that the RCBTB1 gene contains 13 exons and spans 54 kb.
By genomic sequence analysis, Mabuchi et al. (2001) mapped the RCBTB1 gene to chromosome 13q14.
Guo et al. (2004) determined that the C terminus of GLP interacted with the C terminus of AGTR1A. Overexpression of GLP in rat VSMCs and IRPTCs induced cellular hypertrophy. In IRPTCs, the hypertrophic effect was reversed with expression of antisense GLP or a dominant-negative mutant lacking the last 101 amino acids of the C terminus. Angiotensin II (see 106150) stimulated cell hypertrophy in rat IRPTCs by inducing GLP expression, but it could not stimulate hypertrophy in cells expressing antisense GLP or dominant-negative GLP. The hypertrophic effect was mediated at least in part by protein kinase B (see 164730) activation or p27(KIP1) (600778) protein expression.
Retinal Dystrophy with or without Extraocular Anomalies
In 6 families with retinal dystrophy with or without extraocular anomalies involving the thyroid, ovary, and inner ear (RDEOA; 617175), Coppieters et al. (2016) identified homozygosity for missense mutations in the RCBTB1 gene (see, e.g., 607867.0001-607867.0004) that segregated with disease. All of the mutations had a very low minor allele frequency or were not present in the ExAC database.
Associations Pending Confirmation
In 3 affected individuals from 2 unrelated Taiwanese families with eye phenotypes consistent with Coats disease (see 300216) and familial exudative vitreoretinopathy (see EVR2, 305390), Wu et al. (2016) identified heterozygosity for mutations in the RCBTB1 gene. However, in 1 of the families, both affected individuals had inherited the RCBTB1 mutation from their unaffected mothers, and there was also a variant of unknown significance in the NDP gene (300658) segregating in the family. In the second family, the proband had inherited the RCBTB1 mutation from his unaffected father.
In 2 sisters and a maternal cousin (family F1) with retinal dystrophy, goiter, and primary ovarian insufficiency (RDEOA; 617175), Coppieters et al. (2016) identified homozygosity for a c.973C-T transition (rs200826424) in exon 9 of the RCBTB1 gene, resulting in a his325-to-tyr (H325Y) substitution at a highly conserved residue within the sixth repeat of the RCC1-like domain. The mutation segregated with disease in the family and was not found in 142 controls, including 68 of Turkish origin. The authors noted that the variant had an overall allele frequency of 0.0091% in the ExAC database (no homozygotes were observed). Using total RNA from patient peripheral blood mononuclear cells, Coppieters et al. (2016) analyzed mRNA expression of the ubiquitination components CUL3 (603136), RBX1 (603814), and UBE2E3 (604151), as well as the stress-response transcription factor NFE2L2 (600492) and 21 NFE2L2 target genes, and observed significantly decreased expression of CUL3, NFE2L2, and 3 NFE2L2 target genes compared to controls.
In an Italian brother and sister (family F2) and a Greek man (family F3) with progressive retinal dystrophy (RDEOA; 617175), Coppieters et al. (2016) identified homozygosity for a c.919G-A transition (rs368217569) in exon 9 of the RCBTB1 gene, resulting in a val307-to-met (V307M) substitution at a highly conserved residue within the sixth repeat of the RCC1-like domain. The mutation was not present in an unaffected Italian sister. The authors noted that the variant had an overall allele frequency of 0.0025% in the ExAC database. The affected Italian sibs had no reported extraocular anomalies, whereas the Greek man also exhibited thyroid nodules, cold intolerance, and dyslipidemia.
In a Greek father and son (family F4) with progressive retinal dystrophy and adult-onset sensorineural hearing loss (RDEOA; 617175), Coppieters et al. (2016) identified homozygosity for a c.930G-T transversion (c.930G-T, NM_018191.3) in exon 9 of the RCBTB1 gene, resulting in a trp310-to-cys (W310C) substitution at a highly conserved residue within the sixth repeat of the RCC1-like domain. The mutation was also present in an affected paternal aunt and was not found in 3 unaffected relatives. The authors noted that the variant had an overall allele frequency of 0.00083% in the ExAC database.
In a Chinese man (family F6) with progressive retinal dystrophy (RDEOA; 617175), Coppieters et al. (2016) identified homozygosity for a c.1164G-T transversion (c.1164G-T, NM_018191.3) in exon 10 of the RCBTB1 gene, resulting in a leu388-to-phe (L388F) substitution at a highly conserved residue within the first BTB domain. The mutation was not found in the dbSNP, ExAC, or Exome Sequencing Project databases. The patient had no reported extraocular anomalies.
Coppieters, F., Ascari, G., Dannhausen, K., Nikopoulos, K., Peelman, F., Karlstetter, M., Xu, M., Brachet, C., Meunier, I., Tsilimbaris, M. K., Tsika, C., Blazaki, S. V., and 13 others. Isolated and syndromic retinal dystrophy caused by biallelic mutations in RCBTB1, a gene implicated in ubiquitination. Am. J. Hum. Genet. 99: 470-480, 2016. [PubMed: 27486781] [Full Text: https://doi.org/10.1016/j.ajhg.2016.06.017]
Guo, D.-F., Tardif, V., Ghelima, K., Chan, J. S. D., Ingelfinger, J. R., Chen, X., Chenier, I. A novel angiotensin II type 1 receptor-associated protein induces cellular hypertrophy in rat vascular smooth muscle and renal proximal tubular cells. J. Biol. Chem. 279: 21109-21120, 2004. [PubMed: 14985364] [Full Text: https://doi.org/10.1074/jbc.M401544200]
Mabuchi, H., Fujii, H., Calin, G., Alder, H., Negrini, M., Rassenti, L., Kipps, T. J., Bullrich, F., Croce, C. M. Cloning and characterization of CLLD6, CLLD7, CLLD8, novel candidate genes for leukemogenesis at chromosome 13q14, a region commonly deleted in B-cell chronic lymphocytic leukemia. Cancer Res. 61: 2870-2877, 2001. [PubMed: 11306461]
Schrauwen, I., Hasin-Brumshtein, Y., Corneveaux, J. J., Ohmen, J., White, C., Allen, A. N., Lusis, A. J., Van Camp, G., Huentelman, M. J., Friedman, R. A. A comprehensive catalogue of the coding and non-coding transcripts of the human inner ear. Hear. Res. 333: 266-274, 2016. [PubMed: 26341477] [Full Text: https://doi.org/10.1016/j.heares.2015.08.013]
Wu, J.-H., Liu, J.-H., Ko, Y.-C., Wang, C.-T., Chung, Y.-C., Chu, K.-C., Liu, T.-T., Chao, H.-M., Jiang, Y.-J., Chen, S.-J., Chung, M.-Y. Haploinsufficiency of RCBTB1 is associated with Coats disease and familial exudative vitreoretinopathy. Hum. Molec. Genet. 25: 1637-1647, 2016. [PubMed: 26908610] [Full Text: https://doi.org/10.1093/hmg/ddw041]