Alternative titles; symbols
HGNC Approved Gene Symbol: BMS1
SNOMEDCT: 254237003, 35484002; ICD10CM: Q84.8;
Cytogenetic location: 10q11.21 Genomic coordinates (GRCh38): 10:42,782,795-42,834,937 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 10q11.21 | ?Aplasia cutis congenita, nonsyndromic | 107600 | Autosomal dominant | 3 |
Yeast Bms1 regulates cleavage and processing at the A0, A1, and A2 sites of the 35S ribosomal RNA (rRNA) precursor to release mature rRNAs in ribosome biosynthesis (Gelperin et al., 2001).
By sequencing clones obtained from a size-fractionated myeloid leukemia cell line cDNA library, Nagase et al. (1996) cloned BMS1, which they designated KIAA0187. The deduced protein contains 1,285 amino acids. Northern blot analysis detected expression in all tissues examined.
By yeast 2-hybrid screening with Rcl1 (611405), an RNA terminal phosphate cyclase-like protein involved in RNA processing as bait, Wegierski et al. (2001) isolated yeast Bms1. By database analysis, they identified human BMS1. The deduced 1,183-amino acid yeast protein has a calculated molecular mass of 135.5 kD. Yeast and human BMS1 contain a tripartite organization with similar N-terminal and C-terminal domains, separated by a middle region highly enriched in charged amino acids. The N-terminal half of the N-terminal domain contains a G domain similar to that of regulatory GTPases, including the G1, or P-loop, G4, and G5 sequences, and there are 3 nuclear localization signals at the C terminus. Immunofluorescence studies localized yeast Bms1 to the nucleolus.
Gelperin et al. (2001) independently isolated yeast Bms1 in a synthetic lethal screen for mutants sensitive to reduced levels of 14-3-3 proteins (see YWHAH; 113508). Bms1 shares similarity with yeast Tsr1 (611214) across its N-terminal and C-terminal domains.
In mouse embryonic sections showing the site of skin formation at the vertex of the scalp on embryonic day (E) 13.5, Marneros (2013) observed Bms1 expression in all cells, including the proliferative dermis.
By analysis of human-rodent hybrid cell lines, Nagase et al. (1996) mapped the BMS1 gene to chromosome 10.
Wegierski et al. (2001) showed that Bms1 is required for viability in yeast. Using conditional mutant alleles of Bms1, they observed that depletion of Bms1 caused defects in cleavage and processing of yeast 35S pre-rRNA and the disappearance of 40S ribosomal subunits. Glycerol gradient analysis of Bms1 mutants and Rcl1 showed that Bms1 and Rcl1 cosediment together in the 10S complex and associate with nascent ribosomes. Immunoprecipitation studies showed that Bms1 associates with U3 snoRNA. Mutations of BMS1 amino acids implicated in GTP/GDP binding affected BMS1 activity in vivo.
Gelperin et al. (2001) showed that depletion of Bms1 led to a defect in production of 18S rRNA and 40S ribosomal subunits. GST pull-down assays showed that Bms1 bound specifically to GTP and that the P-loop region was required for GTP binding, as P-loop mutation K82A abolished nucleotide binding. Yeast 2-hybrid analysis and GST pull-down assays demonstrated that Bms1 did not interact directly with 14-3-3 proteins.
In affected members of a 5-generation family segregating autosomal dominant aplasia cutis congenita (ACC; 107600), Marneros (2013) identified heterozygosity for a missense mutation in the BMS1 gene (R930H; 611448.0001). Functional analysis of patient fibroblasts showed downregulation of serine/arginine-rich splicing factors and heterogeneous nuclear ribonucleoproteins, and upregulation of p21 (CDKN1A; 116899), leading to G1/S cell cycle phase transition delay and inhibition of cell proliferation.
In a study of 1,751 knockout alleles created by the International Mouse Phenotyping Consortium (IMPC), Dickinson et al. (2016) found that knockout of the mouse homolog of human BMS1 is homozygous-lethal (defined as absence of homozygous mice after screening of at least 28 pups before weaning).
In affected members of a 5-generation family segregating autosomal dominant aplasia cutis congenita (ACC; 107600), Marneros (2013) identified heterozygosity for a c.2789G-A transition in the BMS1 gene, resulting in an arg930-to-his (R930H) substitution at a highly conserved residue within the putative C-terminal GAP domain. The mutation was filtered against the dbSNP (build 129), 1000 Genomes Project, and Exome Sequencing Project databases and was not found in unaffected family members or in 100 ethnically and geographically matched controls. Analysis of labeled pre-rRNAs from patient fibroblasts demonstrated a relative increase in 45S and 30S pre-rRNAs and a relative decrease in 21S and 18S-E pre-rRNAs compared to control fibroblasts, consistent with reduced activity of BMS1 during processing of 18S pre-rRNAs. Patient fibroblasts also showed a p21 (CDKN1A; 116899)-mediated G1/S phase transition defect with a significantly reduced cell proliferation rate compared to controls, and in vitro scratch assay revealed an increased cell migration rate. Western blot analysis confirmed increased p21 protein levels in patient fibroblasts compared to controls. In addition, global quantitative comparative proteomic analysis of patient fibroblasts demonstrated downregulation of serine/arginine-rich splicing factors and heterogeneous nuclear ribonucleoproteins compared to controls.
Dickinson, M. E., Flenniken, A. M., Ji, X., Teboul, L., Wong, M. D., White, J. K., Meehan, T. F., Weninger, W. J., Westerberg, H., Adissu, H., Baker, C. N., Bower, L., and 73 others. High-throughput discovery of novel developmental phenotypes. Nature 537: 508-514, 2016. Note: Erratum: Nature 551: 398 only, 2017. [PubMed: 27626380] [Full Text: https://doi.org/10.1038/nature19356]
Gelperin, D., Horton, L., Beckman, J., Hensold, J., Lemmon, S. K. Bms1p, a novel GTP-binding protein, and the related Tsr1p are required for distinct steps of 40S ribosome biogenesis in yeast. RNA 7: 1268-1283, 2001. [PubMed: 11565749] [Full Text: https://doi.org/10.1017/s1355838201013073]
Marneros, A. G. BMS1 is mutated in aplasia cutis congenita. PLoS Genet. 9: e1003573, 2013. Note: Electronic Article. [PubMed: 23785305] [Full Text: https://doi.org/10.1371/journal.pgen.1003573]
Nagase, T., Seki, N., Ishikawa, K., Tanaka, A., Nomura, N. Prediction of the coding sequences of unidentified human genes. V. The coding sequences of 40 new genes (KIAA0161-KIAA0200) deduced by analysis of cDNA clones from human cell line KG-1. DNA Res. 3: 17-24, 1996. [PubMed: 8724849] [Full Text: https://doi.org/10.1093/dnares/3.1.17]
Wegierski, T., Billy, E., Nasr, F., Filipowicz, W. Bms1p, a G-domain-containing protein, associates with Rcl1p and is required for 18S rRNA biogenesis in yeast. RNA 7: 1254-1267, 2001. [PubMed: 11565748] [Full Text: https://doi.org/10.1017/s1355838201012079]