HGNC Approved Gene Symbol: RPS24
Cytogenetic location: 10q22.3 Genomic coordinates (GRCh38): 10:78,033,863-78,056,806 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 10q22.3 | Diamond-blackfan anemia 3 | 610629 | Autosomal dominant | 3 |
The RPS24 gene encodes a protein involved in ribosomal RNA biogenesis (summary by Choesmel et al., 2008).
Eukaryotic ribosomes are composed of 4 RNA species (see 180450) and at least 80 proteins. Brown et al. (1990) isolated a human ribosomal protein gene encoding a predicted 133-amino acid protein by probing a fibrosarcoma cDNA library with a ribosomal protein gene from Chinese hamster. By comparing the in vitro translation product with S24 from purified ribosomes on 2-dimensional gels, Brown et al. (1990) showed that the gene encodes the 40S ribosomal subunit protein S24 (RPS24).
Xu and Roufa (1996) reported that RPS24 is organized into 6 exons and is differentially spliced to yield 2 isoforms, S24a and S24c, that are present in varying ratios in different tissues.
Jones et al. (1997) used PCR of radiation and somatic cell hybrid panels to map the RPS24 gene to 10q22-q23. Kenmochi et al. (1998) confirmed the RPS24 mapping assignment reported by Jones et al. (1997).
Choesmel et al. (2008) demonstrated that RPS24 is required for the pre-rRNA processing at the 5-prime external transcribed spacer (ETS) of the 45S rRNA precursor molecule.
Crystal Structure
Choesmel et al. (2008) determined the crystal structure of the P. abyssi RPS24e protein, which is homologous to human RPS24. The protein is built around a 4-stranded anti-parallel beta-sheet surrounded by 3 short alpha-helices. It shows homology to the prokaryotic ribosomal protein L23, which is a component of the large ribosomal subunit.
Diamond-Blackfan anemia (DBA) is a rare congenital red cell aplasia characterized by anemia, bone marrow erythroblastopenia, and congenital anomalies. In approximately 25% of probands, heterozygous mutations in the ribosomal protein S19 gene (RPS19; 603474) have been found; see DBA1 (105650). Gazda et al. (2006) reported identification of de novo nonsense and splice site mutations in another ribosomal protein, RPS24 (602412.0001-602412.0003), in approximately 2% of RPS19 mutation-negative probands with Diamond-Blackfan anemia (DBA3; 610629). This finding strongly suggested that DBA is a disorder of ribosome synthesis and that mutations in other ribosomal proteins or associated genes that lead to disrupted ribosomal biogenesis and/or function may also cause DBA.
Choesmel et al. (2008) found that lymphoblastoid cells derived from DBA3 patients with RPS24 mutations (602412.0001-612412.0003) had altered pre-rRNA processing, with lower levels of 41S pre-rRNA and accumulation of the 30S species, resulting in a lower 41S/30S ratio compared to controls. There was also less 21S and 18S-E pre-rRNA compared to controls, but the 21S/18S-E ratio was similar to controls. HeLa cells with siRNA against RPS24 showed a loss of free 40S ribosomal subunits and an accumulation of 60S subunits, indicating that RPS24 is essential for the production of the small ribosomal subunit 40S. Pulse-chase labeling and Northern blot studies of siRNA-knockdown cells showed lack of formation of 41S, 21S, and 18S-E pre-rRNA, although 28S was normal and 30S was increased. These findings suggested inhibition of cleavage at the 5-prime external transcribed spacer (ETS), as well as blocking of the subsequent processing of internal spacer-1 (ITS1) at the 3-prime end of the 18S rRNA. The pattern of the 60S rRNA subunit was normal, as were patterns of 28S and 5.8S rRNAs. RPS19 was also decreased, likely due to impaired synthesis of the 40S subunit. The pattern resulting from RPS24 depletion was similar to that of RPS19 depletion, in that depletion of RPS19 results in delayed maturation of the 40S subunit (Flygare et al., 2007). However, RPS19 depletion resulted in increased 41S and 21S pre-rRNAs levels, consistent with a defect in processing at ITS1. Studies combining deletions of RPS24 and RPS19 indicated that the 2 exert interdependent functions in pre-rRNA processing. Choesmel et al. (2008) concluded that mutations in the RPS24 gene result in haploinsufficiency, and that the pathogenesis of DBA is related to defective ribosome biogenesis, which may result in apoptosis of rapidly proliferating cells such as erythroid precursors.
Landowski et al. (2013) performed array CGH for copy number variation in 87 probands with Diamond-Blackfan anemia who were negative for mutation in 10 known DBA-associated ribosomal protein genes and identified a large de novo deletion in the RPS24 gene (602412.0004) in a steroid-dependent male patient.
In a family with Diamond-Blackfan anemia (DBA3; 610629) in an autosomal dominant pedigree pattern, Gazda et al. (2006) found a heterozygous transition in exon 4 of the RPS24 gene, 316C-T, in affected individuals that gave rise to a substitution of a stop codon for gln106 (Q106X). Three members of the family were affected. Older members presented with severe anemia and were dependent on small doses of steroid. Another patient had been in steroid-induced remission since childhood and presented with webbed neck.
In a sporadic case of Diamond-Blackfan anemia (DBA3; 610629), Gazda et al. (2006) identified a nonsense mutation, arg16 to stop, in the RPS24 gene. The amino acid substitution arose from a C-to-T transition at nucleotide 46 in exon 2.
In a family with 2 members affected by Diamond-Blackfan anemia (DBA3; 610629), Gazda et al. (2006) identified a deletion/insertion at the intron 1/exon 2 boundary of RPS24 that resulted in skipping of exon 2 with deletion of 22 amino acids.
In a steroid-dependent male patient with Diamond-Blackfan anemia (DBA3; 610629), Landowski et al. (2013) identified heterozygosity for a de novo 5,134-bp deletion at chr10:79,460,166-79,465,299 (NCBI36), containing exons 1 and 2 as well as part of exon 3 of the RPS24 gene. Validation using mPCR assay showed confirmed reduction of PCR product for exons 1 to 3; mPCR in his unaffected parents showed ratios similar to controls, indicating that the deletion occurred de novo.
Brown, S. J., Jewell, A., Maki, C. G., Roufa, D. J. A cDNA encoding human ribosomal protein S24. Gene 91: 293-296, 1990. [PubMed: 2210388] [Full Text: https://doi.org/10.1016/0378-1119(90)90103-x]
Choesmel, V., Fribourg, S., Aguissa-Toure, A.-H., Pinaud, N., Legrand, P., Gazda, H. T., Gleizes, P.-E. Mutation of ribosomal protein RPS24 in Diamond-Blackfan anemia results in a ribosome biogenesis disorder. Hum. Molec. Genet. 17: 1253-1263, 2008. [PubMed: 18230666] [Full Text: https://doi.org/10.1093/hmg/ddn015]
Flygare, J., Aspesi, A., Bailey, J. C., Miyake, K., Caffrey, J. M., Karlsson, S., Ellis, S. R. Human RPS19, the gene mutated in Diamond-Blackfan anemia, encodes a ribosomal protein required for the maturation of 40S ribosomal subunits. Blood 109: 980-986, 2007. [PubMed: 16990592] [Full Text: https://doi.org/10.1182/blood-2006-07-038232]
Gazda, H. T., Grabowska, A., Merida-Long, L. B., Latawiec, E., Schneider, H. E., Lipton, J. M., Vlachos, A., Atsidaftos, E., Ball, S. E., Orfali, K. A., Niewiadomska, E., Da Costa, L., and 11 others. Ribosomal protein S24 gene is mutated in Diamond-Blackfan anemia. Am. J. Hum. Genet. 79: 1110-1118, 2006. [PubMed: 17186470] [Full Text: https://doi.org/10.1086/510020]
Jones, A.-M., Marzella, R., Rocchi, M., Hewitt, J. E. Mapping of the human ribosomal small subunit protein gene RPS24 to the chromosome 10q22-q23 boundary. Genomics 39: 121-122, 1997. [PubMed: 9027498] [Full Text: https://doi.org/10.1006/geno.1996.4442]
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]
Xu, W.-B., Roufa, D. J. The gene encoding human ribosomal protein S24 and tissue-specific expression of differentially spliced mRNAs. Gene 169: 257-262, 1996. [PubMed: 8647458] [Full Text: https://doi.org/10.1016/0378-1119(96)88652-5]