HGNC Approved Gene Symbol: RPL15
Cytogenetic location: 3p24.2 Genomic coordinates (GRCh38) : 3:23,916,545-23,924,631 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 3p24.2 | Diamond-Blackfan anemia 12 | 615550 | Autosomal dominant | 3 |
The mammalian ribosome is composed of 4 RNA species (see 180450) and approximately 80 different proteins (see 180466).
Adams et al. (1992) isolated an RPL15 cDNA as a human brain EST that shows sequence similarity to the yeast ribosomal protein YL10 gene.
The complete coding sequence of the human RPL15 gene has been deposited in GenBank (L25899). The deduced RPL15 protein has 205 amino acids.
In mice, Ebright et al. (2020) conducted an in vivo genomewide CRISPR activation screen in circulating tumor cells from breast cancer patients to identify genes that promote distant metastasis. Genes coding for ribosomal proteins and regulators of translation were enriched in this screen. Overexpression of RPL15 increased metastatic growth in multiple organs and selectively enhanced translation of other ribosomal proteins and cell cycle regulators. RNA sequencing of freshly isolated circulating tumor cells from breast cancer patients revealed a subset with strong ribosome and protein synthesis signatures; these circulating tumor cells expressed proliferation and epithelial markers and correlated with poor clinical outcome.
By somatic cell hybrid and radiation hybrid mapping analyses, Kenmochi et al. (1998) mapped the human RPL15 gene to 3p.
Gross (2013) mapped the RPL15 gene to chromosome 3p24.2 based on an alignment of the RPL15 sequence (GenBank AF279903) with the genomic sequence (GRCh37).
Landowski et al. (2013) performed array CGH for copy number variation in 87 probands with Diamond-Blackfan anemia (DBA12; 615550) who were negative for mutation in 10 known DBA-associated ribosomal protein genes, and identified a large deletion in the RPL15 gene in 1 patient (604174.0001).
Wlodarski et al. (2018) identified heterozygous nonsense and missense mutations in the RPL15 gene in 6 unrelated patients with DBA12 (604174.0002-604174.0005). One of the nonsense mutations (Y81X; 604174.0002) was found in 3 patients. The mutations were identified by Sanger sequencing of the RPL15 gene in a cohort of 985 patients with DBA without a molecular diagnosis. Lymphoblastoid cells from 2 of the patients with the Y81X mutation showed impaired pre-rRNA processing, decreased 60S ribosomal subunit formation, and deficient cell proliferation. Bone marrow mononuclear cells from these 2 patients also showed increased TP53-induced apoptosis and increased p21 mRNA and delayed erythrocyte maturation compared to wildtype cells.
Wlodarski et al. (2018) identified heterozygous nonsense mutations in the RPL15 gene in 4 unrelated patients with DBS12, 3 with a Y81X mutation (604174.0002) and 1 with a Q29X mutation (604174.0003). Three of these patients had hydrops fetalis, which is a rare presentation in DBA. The 3 patients with a Y81X mutation achieved rapid treatment independence, both with or without steroid therapy. This treatment independence was not due to gene mutation reversion.
In a female patient with Diamond-Blackfan anemia (DBA12; 615550), Landowski et al. (2013) identified heterozygosity for a 2,393-bp deletion at chr3:23,935,161-23,937,553 (NCBI36), containing all of exon 4 of the RPL15 gene (EX4DEL). Validation by mPCR showed that only the PCR product from exon 4 was significantly decreased; mPCR in unaffected family members showed ratios more similar to controls than to the proband. Functional analysis by knockdown of RPL15 in HeLa cells showed a drop in free 60S ribosomal subunits and the appearance of half-mers in the polysome profile, characteristic of defective 60S subunit production. There were also decreased levels of 32S and 12S pre-rRNAs, precursors to the 5.8S and 28S rRNAs. In addition, there was accumulation of the 41S, 30S, and 18S-E pre-rRNAs relative to the 21S pre-rRNA, suggesting a defect in internal transcribed spacer-1 (ITS1) cleavage at site 2. Analysis of RNA from patient lymphoblastoid cell lines showed a pattern consistent with the findings in the knocked-down HeLa cells, strongly suggesting that the RPL15 deletion affects pre-rRNA processing in patient cells.
In 3 unrelated patients (patients 1-3) with Diamond-Blackfan anemia (DBA12; 615550), Wlodarski et al. (2018) identified heterozygosity for a 1-bp duplication (c.242dupA, NM_001253379.1) in the RPL15 gene, resulting in a tyr81-to-ter (Y81X) substitution. The mutation was identified by Sanger sequencing of the RPL15 gene in a cohort of patients with DBA without a molecular diagnosis. The father of one of the patients (patient 1) also carried the mutation and was determined to be a silent carrier due to high erythrocyte adenosine deaminase levels. The mutation occurred de novo in the other 2 patients. The variant was not present in the ExAC and gnomAD databases. Lymphoblastoid cells from 2 of the patients showed impaired pre-rRNA processing, decreased 60S ribosomal subunit formation, and deficient cell proliferation.
In a patient (patient 4) with Diamond-Blackfan anemia (DBA12; 615550), Wlodarski et al. (2018) identified heterozygosity for a c.85C-T transition (c.85C-T, NM_001253379.1) in the RPL15 gene, resulting in a gln29-to-ter (Q29X) substitution. The mutation was identified by Sanger sequencing of the RPL15 gene in a cohort of patients with DBA without a molecular diagnosis. The parents were not tested for the mutation. The variant was not present in the ExAC and gnomAD databases.
In a patient (patient 5) with Diamond-Blackfan anemia (DBA12; 615550), Wlodarski et al. (2018) identified heterozygosity for a c.29T-C transition (c.29T-C, NM_001253379.1) in the RPL15 gene, resulting in a leu10-to-pro (L10P) substitution at a conserved site. The mutation was identified by Sanger sequencing of the RPL15 gene in a cohort of patients with DBA without a molecular diagnosis. The mutation was inherited from the patient's mother. The variant was not present in the ExAC and gnomAD databases.
In a patient (patient 6) with Diamond-Blackfan anemia (DBA12; 615550), Wlodarski et al. (2018) identified heterozygosity for a c.458A-C transversion (c.458A-C, NM_001253379.1) in the RPL15 gene, resulting in a lys153-to-thr (K153T) substitution at a conserved site. The mutation was identified by Sanger sequencing of the RPL15 gene in a cohort of patients with DBA without a molecular diagnosis. The parents were not tested for the mutation. The variant was present in 33 of 232,840 alleles in the gnomAD database.
Adams, M. D., Dubnick, M., Kerlavage, A. R., Moreno, R., Kelley, J. M., Utterback, T. R., Nagle, J. W., Fields, C., Venter, J. C. Sequence identification of 2,375 human brain genes. Nature 355: 632-634, 1992. Note: Comment: Nature 357: 367-368, 1992. [PubMed: 1538749] [Full Text: https://doi.org/10.1038/355632a0]
Ebright, R. Y., Lee, S., Wittner, B. S., Niederhoffer, K. L., Nicholson, B. T., Bardia, A., Truesdell, S., Wiley, D. F., Wesley, B., Li, S., Mai, A., Aceto, N., and 13 others. Deregulation of ribosomal protein expression and translation promotes breast cancer metastasis. Science 367: 1468-1473, 2020. [PubMed: 32029688] [Full Text: https://doi.org/10.1126/science.aay0939]
Gross, M. B. Personal Communication. Baltimore, Md. 12/19/2013.
Kenmochi, N., Kawaguchi, T., Rozen, S., Davis, E., Goodman, N., Hudson, T. J., Tanaka, T., Page, D. C. A map of 75 human ribosomal protein genes. Genome Res. 8: 509-523, 1998. [PubMed: 9582194] [Full Text: https://doi.org/10.1101/gr.8.5.509]
Landowski, M., O'Donohue, M.-F., Buros, C., Ghazvinian, R., Montel-Lehry, N., Vlachos, A., Sieff, C. A., Newburger, P. E., Niewiadomska, E., Matysiak, M., Glader, B., Atsidaftos, E., Lipton, J. M., Beggs, A. H., Gleizes, P.-E., Gazda, H. T. Novel deletion of RPL15 identified by array-comparative genomic hybridization in Diamond-Blackfan anemia. Hum. Genet. 132: 1265-1274, 2013. [PubMed: 23812780] [Full Text: https://doi.org/10.1007/s00439-013-1326-z]
Wlodarski, M. W., Da Costa, L., O'Donohue, M. F., Gastou, M., Karboul, N., Montel-Lehry, N., Hainmann, I., Danda, D., Szvetnik, A., Pastor, V., Paolini, N., di Summa, F. M., Tamary, H., Quider, A. A., Aspesi, A., Houtkooper, R. H., Leblanc, T., Niemeyer, C. M., Gleizes, P. E., MacInnes, A. W. Recurring mutations in RPL15 are linked to hydrops fetalis and treatment independence in Diamond-Blackfan anemia. Haematologica 103: 949-958, 2018. [PubMed: 29599205] [Full Text: https://doi.org/10.3324/haematol.2017.177980]