Alternative titles; symbols
HGNC Approved Gene Symbol: RBM8A
SNOMEDCT: 85589009; ICD10CM: Q87.2;
Cytogenetic location: 1q21.1 Genomic coordinates (GRCh38) : 1:145,921,556-145,927,484 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1q21.1 | Thrombocytopenia-absent radius syndrome | 274000 | Autosomal recessive | 3 |
The RBM8A gene encodes Y14, 1 of the 4 components of the exon-junction complex (EJC), which is involved in basic cellular functions such as nuclear export and subcellular localization of specific transcripts, translational enhancement, and nonsense-mediated RNA decay (NMD) (summary by Albers et al., 2012).
Mago nashi (MAGOH; 602603), meaning grandchildless, is the homolog of a Drosophila protein required for normal germ plasm development in fly embryos. By performing a yeast 2-hybrid screen on a fetal brain cDNA library with MAGOH as the bait, Zhao et al. (2000) recovered a cDNA encoding RBM8. The 173-amino acid RBM8 protein is more than 93% identical to the mouse and zebrafish sequences, and the mouse differences are all accounted for by an 11-amino acid N-terminal insertion and another single-residue insertion in the mouse sequence. Exchange partner and GST pull-down assays confirmed the MAGOH-RBM8 interaction and showed that RBM8 is expressed as a 26-kD protein, slightly larger than the predicted mass of 23 kD. Northern blot analysis detected a major RBM8 transcript of less than 1.0 kb in all tissues tested, with weakest expression in pancreas and brain.
By searching an EST database for homologs of the gonadotropin-releasing hormone receptor (GNRHR; 138850), followed by 5-prime RACE on a skeletal muscle cDNA library, Conklin et al. (2000) identified a cDNA encoding RBM8. Northern blot analysis detected a major 0.9-kb transcript in all tissues tested. Sequence analysis of the 174-amino acid protein predicted an RNA-binding domain, which is composed of 2 amphipathic alpha helices packed against a 4-stranded beta sheet, and a C-terminal arg-rich segment.
By performing a yeast 2-hybrid screen on a HeLa cell cDNA library to identify potential cargoes for RAN-binding protein-5 (RANBP5; 602008), Kataoka et al. (2000) isolated cDNAs encoding RBM8, which they called Y14. RBM8 encodes a predicted 174-amino acid, predominantly nuclear nucleocytoplasmic shuttling protein.
Salicioni et al. (2000) used a yeast 2-hybrid screen to identify cDNAs from a human fetal brain cDNA library encoding proteins that interact with OVCA1 (603527), a candidate tumor suppressor protein. They identified cDNAs, which they initially referred to as BOV1, that appeared to encode a new member of the conserved RNA-binding motif protein family. One of the cDNAs isolated was identical to RBM8A; another, designated RBM8B, was thought by Salicioni et al. (2000) to be a novel functional gene, but was later determined to be a pseudogene. Northern blot analysis revealed that BOV1 is ubiquitously expressed as 3 distinct mRNA species of 1, 3.2, and 5.8 kb.
Kataoka et al. (2000) found that RBM8 associates preferentially with mRNAs produced by splicing and not with pre-mRNAs, introns, or mRNAs produced from intronless cDNAs. RBM8 associates with both nuclear mRNAs and newly exported cytoplasmic mRNAs. Splicing of a single intron is sufficient for RBM8 association. RBM8-containing nuclear complexes are different from general heterogeneous nuclear ribonucleoprotein (hnRNP) complexes in that they contain hnRNP proteins and several unique proteins, including the mRNA export factor TAP (NXF1; 602647). Thus, RBM8 defines novel intermediates in the pathway of gene expression, postsplicing nuclear preexport mRNPs, and newly exported cytoplasmic mRNPs, whose composition is established by splicing. These findings suggested that pre-mRNA splicing imprints mRNA with a unique set of proteins that persists in the cytoplasm and thereby communicates the history of the transcript.
Kim et al. (2001) analyzed the binding of RBM8A, which they called Y14, to pre-mRNAs injected into nuclei of Xenopus oocytes. They found that RBM8A stably bound mRNA sequences approximately -20 nucleotides upstream of exon-exon junctions.
Oskar mRNA localization at the posterior pole of the Drosophila oocyte is essential for germline and abdomen formation in the future embryo. Y14/RBM8 and MAGOH (602603), human homologs of nuclear shuttling proteins required for oskar mRNA localization, are core components of the exon-exon junction complex (EJC). The EJC is deposited on mRNAs in a splicing-dependent manner, 20 to 24 nucleotides upstream of exon-exon junctions, independent of the RNA sequence. This indicates a possible role of splicing in oskar mRNA localization, challenging the established notion that the oskar 3-prime untranslated region is sufficient for this process. Hachet and Ephrussi (2004) demonstrated that splicing at the first exon-exon junction of oskar RNA is essential for oskar mRNA localization at the posterior pole. They revisited the issue of sufficiency of the oskar 3-prime untranslated region for posterior localization and showed that the localization of unrelated transcripts bearing the oskar 3-prime untranslated region is mediated by endogenous oskar mRNA. Hachet and Ephrussi (2004) concluded that their results revealed an important new function for splicing: regulation of messenger ribonucleoprotein complex assembly and organization for mRNA cytoplasmic localization.
Albers et al. (2012) showed that RBM8A is expressed in all hematopoietic lineages, and that its encoded protein sequence is highly conserved between species. Albers et al. (2012) suggested that, given the important functions of the EJC, it is likely that a complete lack of Y14 in humans is not viable. Indeed, in Drosophila melanogaster, knockdown of its ortholog tsu leads to major defects in abdomen formation (Hachet and Ephrussi, 2001), and Albers et al. (2012) found that knockdown of the orthologous rbm8a transcript in Danio rerio using antisense morpholinos resulted in extreme malformations and death at 2 days post-fertilization.
Albers et al. (2012) determined that the RBM8A gene comprises 6 exons.
By PCR and radiation hybrid analysis, Zhao et al. (2000) mapped the RBM8A gene to 1q12. Conklin et al. (2000) mapped the RBM8 gene to 14q21-q23 using radiation hybrid analysis, but it appears that the sequence on chromosome 14 is a pseudogene.
It had been shown that an inherited or de novo deletion on chromosome 1q21.1 (Klopocki et al., 2007) is found in the majority of individuals with TAR syndrome (274000), but the apparent autosomal recessive nature of that syndrome required the existence of an additional causative allele. To identify the additional causative allele, Albers et al. (2012) selected 5 individuals with TAR of European ancestry who had the 1q21.1 deletion and sequenced their exomes, but were unable to find TAR-associated coding mutations in any gene. However, 4 of the cases carried the minor allele of a low-frequency SNP in the 5-prime UTR of the RBM8A gene (rs139428292; 605313.0001), while the remaining case carried a previously unknown SNP in the first intron of the same gene (605313.0002). Genotyping by Sanger sequencing of another 48 cases of European ancestry identified the 2 SNPs in 35 and 11 samples, respectively. In the 25 trios where the deletion in the child was not a de novo event, Albers et al. (2012) confirmed that the deletion and the newly identified SNPs were inherited from different parents. The minor allele frequency of the 5-prime UTR and intronic SNPs were 3.05% and 0.42%, respectively, in 7,504 healthy individuals of the Cambridge BioResource, and the deletion was absent from 5,919 shared healthy controls of the Wellcome Trust Case Control Consortium. There were 2 TAR cases who did not carry the 1q21.1 deletion but were found to carry the 5-prime UTR SNP. Albers et al. (2012) identified a 4-bp frameshift insertion at the start of the fourth exon (605313.0003) in the first case and established that the noncoding SNP and insertion were on different chromosomes; in the second case, they identified a nonsense mutation in the last exon of RBM8A (605313.0004). Both mutations were absent from 458 exome samples of the 1000 Genomes Project and 416 samples from the Cohorte Lausannoise. Albers et al. (2012) concluded that in the vast majority of cases, compound inheritance of a rare null allele (containing a deletion, frameshift mutation, or encoded premature stop codon) and 1 of 2 low-frequency noncoding SNPs in RBM8A causes TAR syndrome. Albers et al. (2012) showed that the 2 regulatory SNPs result in diminished RBM8A transcription in vitro and that expression of Y14 is reduced in platelets from individuals with TAR. Albers et al. (2012) concluded that their data implicated Y14 insufficiency and, presumably, an EJC defect as the cause of TAR syndrome.
Given the expression of Y14 in hematopoietic lineages and major defects observed in Drosophila and zebrafish resulting from knockdown of the respective Y14 orthologs, Albers et al. (2012) suggested that their results are compatible with both a dose-effect phenomenon and a lineage-dependent deficiency in Y14. The possibility of a dose-effect phenomenon was supported by the observation that simple haploinsufficiency is not sufficient to create an aberrant phenotype, as evidenced by the seemingly healthy carriers of the 1q21.1 deletion. Albers et al. (2012) did not observe an effect on platelet count for either the 5-prime UTR or the intronic SNP in the 403 and 59 individuals from the Cambridge BioResource who carried the minor allele for each SNP, respectively. The authors suggested that compound inheritance of a null allele together with the minor allele of 1 of the 2 regulatory SNPs brings Y14 levels below a critical threshold in certain tissues. The cell line-dependent effect shown in luciferase assays suggested a combinatorial binding of transcription factors, including EVI1 (165215), in the context of regulatory SNPs.
In 41 of 55 patients with thrombocytopenia-absent radius syndrome (TAR; 274000), Albers et al. (2012) identified the presence of the minor allele (A) of a G-to-A SNP, rs139428292 (chr1:145,507,646, GRCh37), in the 5-prime untranslated region (UTR) of the RBM8A gene. In 39 of these patients this SNP was found in compound heterozygosity with a 200-kb deletion including the RBM8A gene and 10 other genes; in 2 patients the SNP occurred in compound heterozygosity with 1 of 2 null mutations in the RBM8A gene. The minor allele frequency of the SNP rs139428292 was 3.05% in 7,504 healthy individuals of the Cambridge BioResource. This SNP resulted in diminished RBM8A transcription in vitro.
In 12 of 55 patients with thrombocytopenia-absent radius syndrome (TAR; 274000), Albers et al. (2012) identified the presence of the minor allele (C) of a SNP in the first intron of the RBM8A gene (chr1:145,507,765, GRCh37). The SNP occurred in compound heterozygosity with a 200-kb deletion including the RBM8A gene and 10 other genes. The minor allele frequency of this intronic SNP was 0.42% in 7,504 healthy individuals of the Cambridge BioResource. This SNP resulted in diminished RBM8A transcription in vitro.
In a patient with thrombocytopenia-absent radius syndrome (TAR; 274000), Albers et al. (2012) found compound heterozygosity for a 4-bp insertion (AGCG, chr1:145,508,476, GRCh37) in exon 4 of the RBM8A gene, resulting in frameshift, and a SNP in the 5-prime UTR (605313.0001).
In a patient with thrombocytopenia-absent radius syndrome (TAR; 274000), Albers et al. (2012) found compound heterozygosity for a premature termination mutation in the last exon of the RBM8A gene (C-T, chr1:145,509,173, GRCh37) and a SNP in the 5-prime UTR (605313.0001).
Albers, C. A., Paul, D. S., Schulze, H., Freson, K., Stephens, J. C., Smethurst, P. A., Jolley, J. D., Cvejic, A., Kostadima, M., Bertone, P., Breuning, M. H., Debili, N., and 19 others. Compound inheritance of a low-frequency regulatory SNP and a rare null mutation in exon-junction complex subunit RBM8A causes TAR syndrome. Nature Genet. 44: 435-439, 2012. [PubMed: 22366785] [Full Text: https://doi.org/10.1038/ng.1083]
Conklin, D. C., Rixon, M. W., Kuestner, R. E., Maurer, M. F., Whitmore, T. E., Millar, R. P. Cloning and gene expression of a novel human ribonucleoprotein. Biochim. Biophys. Acta 1492: 465-469, 2000. [PubMed: 11004516] [Full Text: https://doi.org/10.1016/s0167-4781(00)00090-7]
Hachet, O., Ephrussi, A. Drosophila Y14 shuttles to the posterior of the oocyte and is required for oskar mRNA transport. Curr. Biol. 11: 1666-1674, 2001. [PubMed: 11696323] [Full Text: https://doi.org/10.1016/s0960-9822(01)00508-5]
Hachet, O., Ephrussi, A. Splicing of oskar RNA in the nucleus is coupled to its cytoplasmic localization. Nature 428: 959-963, 2004. [PubMed: 15118729] [Full Text: https://doi.org/10.1038/nature02521]
Kataoka, N., Yong, J., Kim, V. N., Velazquez, F., Perkinson, R. A., Wang, F., Dreyfuss, G. Pre-mRNA splicing imprints mRNA in the nucleus with a novel RNA-binding protein that persists in the cytoplasm. Molec. Cell 6: 673-682, 2000. [PubMed: 11030346] [Full Text: https://doi.org/10.1016/s1097-2765(00)00065-4]
Kim, V. N., Yong, J., Kataoka, N., Abel, L., Diem, M. D., Dreyfuss, G. The Y14 protein communicates to the cytoplasm the position of exon-exon junctions. EMBO J. 20: 2062-2068, 2001. [PubMed: 11296238] [Full Text: https://doi.org/10.1093/emboj/20.8.2062]
Klopocki, E., Schulze, H., Strauss, G., Ott, C.-E., Hall, J., Trotier, F., Fleischhauer, S., Greenhalgh, L., Newbury-Ecob, R. A., Neumann, L. M., Habenicht, R., Konig, R., Seemanova, E., Megarbane, A., Ropers, H.-H., Ullmann, R., Horn, D., Mundlos, S. Complex inheritance pattern resembling autosomal recessive inheritance involving a microdeletion in thrombocytopenia-absent radius syndrome. Am. J. Hum. Genet. 80: 232-240, 2007. [PubMed: 17236129] [Full Text: https://doi.org/10.1086/510919]
Salicioni, A. M., Xi. M., Vanderveer, L. A., Balsara, B., Testa, J. R., Dunbrack, R. L., Jr., Godwin, A. K. Identification and structural analysis of human RBM8A and RBM8B: two highly conserved RNA-binding motif proteins that interact with OVCA1, a candidate tumor suppressor. Genomics 69: 54-62, 2000. [PubMed: 11013075] [Full Text: https://doi.org/10.1006/geno.2000.6315]
Zhao, X.-F., Nowak, N. J., Shows, T. B., Aplan, P. D. MAGOH interacts with a novel RNA-binding protein. Genomics 63: 145-148, 2000. [PubMed: 10662555] [Full Text: https://doi.org/10.1006/geno.1999.6064]