HGNC Approved Gene Symbol: RPL5
Cytogenetic location: 1p22.1 Genomic coordinates (GRCh38) : 1:92,831,986-92,841,924 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1p22.1 | Diamond-Blackfan anemia 6 | 612561 | Autosomal dominant | 3 |
The mammalian ribosome is a macromolecular assembly of 4 RNA species (rRNAs; see 180450) and approximately 80 different proteins, including RPL5 (Kenmochi et al., 1998).
By searching sequence databases with the partial sequences of randomly selected cDNAs from a human colorectal cDNA library, Frigerio et al. (1995) identified cDNAs encoding homologs of rat ribosomal proteins S5 (RPS5; 603630), S9 (RPS9; 603631), S10 (RPS10; 603632), S29 (RPS29; 603633), L5 (RPL5), L21 (RPL21; 603636), L27a (RPL27A; 603637), and L28 (RPL28; 603638). Frigerio et al. (1995) completed the cDNA sequences of these human ribosomal proteins. The deduced 297-amino acid human RPL5 differs from rat Rpl5 by 4 amino acids. Northern blot analysis suggested variable expression of RPL5 in colorectal cancers compared to adjacent normal tissues, although no correlation between the level of expression and the severity of the disease was found.
By Northern blot analysis using a rat Rpl5 probe, Pogue-Geile et al. (1991) demonstrated overexpression of RPL5 in human colorectal tumors and polyps relative to matched normal colonic mucosa. RPL5 is expressed as a 1.2-kb transcript.
Boria et al. (2010) stated that the RPL5 gene contains 8 exons and spans 9.8 kb.
In both human and mouse, Qu et al. (1994) found that the U21 snoRNA (603635) is encoded in intron 5 of the RPL5 gene.
By somatic cell hybrid and radiation hybrid mapping analyses, Kenmochi et al. (1998) mapped the RPL5 gene to chromosome 1p.
Boria et al. (2010) stated that the RPL5 gene maps to chromosome 1p22.1.
Impeding ribosomal biogenesis generates ribosomal stress that activates p53 (TP53; 191170) to stop cell growth. Dai et al. (2006) stated that the ribosomal proteins L5, L11 (RPL11; 604175), and L23 (RPL23; 603662) interact with MDM2 (164785) and inhibit MDM2-mediated p53 ubiquitination and degradation in response to ribosomal stress. They found that L5 and L23 inhibited ubiquitination of both p53 and MDM2 in human cell lines. In contrast, L11 inhibited proteasome-mediated degradation of ubiquitinated MDM2, but not p53, resulting in stabilization of p53.
Ribosomal protein L5 binds 5S rRNA (see 180420) to form the ribosomal 5S RNA-protein (5S rRNP) complex. Using polysome assays and crosslinking experiments with in vitro-translated human mRNA, Lin et al. (2001) found that the 5S rRNP complex formed only if 5S rRNA was present at the beginning of L5 translation. The 5S rRNP complex was not observed if 5S rRNA was added after completion of L5 synthesis. Mutation analysis revealed that residues 35 through 50 of L5 engaged in the interaction, but the remainder of the L5 protein was required for stable formation of the 5S rRNP complex. Association of L5 with 5S rRNA significantly enhanced L5 nuclear import into injected Xenopus oocytes.
Gazda et al. (2008) screened 196 probands with Diamond-Blackfan anemia (see DBA6, 612561) for mutations in 25 genes encoding ribosomal proteins and identified 15 different mutations in the RPL5 gene in 18 probands and 6 additional family members (see, e.g., 603634.0001-603634.0006); 3 of the mutation-positive patients were from the family with DBA originally described by Aase and Smith (1969) (see 603634.0005). The mutations segregated with disease in multiplex families and were not found in at least 150 controls. Analysis of pre-rRNAs from lymphoblastoid cells established from DBA patients revealed accumulation of 32S and 12S pre-rRNA as well as smaller precursors of 5.8S rRNA compared to controls, indicating defective maturation of internal transcribed spacer-2 (ITS2) both at the initial endonucleolytic cleavage in the 32S pre-rRNA and during subsequent processing steps.
Gerrard et al. (2013) identified 4 different heterozygous truncating mutations in the RPL5 gene (see, e.g., 603634.0007 and 603634.0008) in 5 of 19 patients with DBA who were screened for mutations in 80 ribosomal protein genes.
Somatic Mutation in T-Cell ALL
De Keersmaecker et al. (2013) identified mutations in the ribosomal protein RPL5 in 4 of 211 (1.9%) pediatric and adult T-cell ALLs.
In a female patient in whom Diamond-Blackfan anemia (DBA6; 612561) was diagnosed at 2 months of age, who also had cleft lip and palate, Gazda et al. (2008) identified heterozygosity for a de novo 67C-T transition in exon 2 of the RPL5 gene, resulting in an arg23-to-ter (R23X) substitution. The mutation was not found in her unaffected parents or in at least 150 controls.
In a male patient in whom Diamond-Blackfan anemia (DBA6; 612561) was diagnosed at 3 months of age, who had no associated malformations, Gazda et al. (2008) identified heterozygosity for a 418G-A transition in exon 5 of the RPL5 gene, resulting in a gly140-to-ser (G140S) substitution. The mutation was also identified in his father, who did not have anemia, but was not found in his unaffected mother or 2 sibs or in at least 150 controls.
In 1 female and 2 male patients with Diamond-Blackfan anemia (DBA6; 612561), 2 of whom were known to have multiple associated anomalies, Gazda et al. (2008) identified heterozygosity for a 2-bp deletion (173delGA) in exon 3 of the RPL5 gene, resulting in a frameshift causing a termination sequence at codon 111. Associated features in 1 of the male patients included bilateral long proximal thumb phalanges and multiple congenital heart defects, including double outlet right ventricle, pulmonary stenosis, left pulmonary artery stenosis, and patent ductus arteriosus; the other male patient had a small jaw, cleft palate, bronchiopharyngeal malacia, and mild hydrocephalus; clinical information was not available for the female patient. The mutation was not found in the unaffected parents or 2 sibs of the female patient, or in at least 150 controls.
In 2 female patients with Diamond-Blackfan anemia (DBA6; 612561), both of whom had associated anomalies, Gazda et al. (2008) identified heterozygosity for a 1-bp insertion (235insT) in exon 4 of the RPL5 gene, resulting in a frameshift causing a termination sequence at codon 112. One of the patients also had cleft soft palate, and the other had cleft palate, bifid uvula, and hypoplastic thumb. The mutation was identified in the mothers of both patients, respectively, both of whom had macrocytic anemia with no associated anomalies, and the mutation was not found in at least 150 controls.
In affected members of a family with Diamond-Blackfan anemia (DBA6; 612561) and associated triphalangeal thumbs, originally reported by Aase and Smith (1969), Gazda et al. (2008) identified heterozygosity for a 5-bp deletion/39-bp insertion (498delTGTGGins39) in exon 5 of the RPL5 gene, resulting in frameshift and premature termination of the protein at codon 216. The male proband had ventricular septal defect in addition to triphalangeal thumbs; the mutation was also identified in his affected brother, who had cleft lip and triphalangeal thumbs, and in his affected daughter, for whom phenotype information was unavailable. The mutation was not found in the proband's unaffected parents or sister, or in at least 150 controls.
In a male patient with Diamond-Blackfan anemia (DBA6; 612561) who had no associated malformations, Gazda et al. (2008) identified heterozygosity for a de novo T-G transversion at the donor splice site in intron 2 (IVS2DS+2T-G) of the RPL5 gene, resulting in premature termination of the protein. The mutation was not found in patient's unaffected parents or brother, or in at least 150 controls.
In a mother and daughter with DBA6 (612561), Gerrard et al. (2013) identified a heterozygous c.244G-T transversion in exon 4 of the RPL5 gene, resulting in a glu82-to-ter (E82X) substitution. The 39-year-old mother was diagnosed at 5 years of age. She had growth retardation, osteoporosis, thumb abnormalities, and hepatic iron overload. Her 10-year-old daughter had intrauterine growth retardation and dental distress, and was diagnosed at birth. She had Cathie facies, cleft palate, ventricular septal defect, vitamin D deficiency, and iron overload. Both had increased erythrocyte adenosine deaminase (ADA; 608958). The mother's disorder was steroid-responsive, whereas the daughter developed secondary steroid resistance.
In a 4-year-old Caucasian boy with DBA6 (612561), Gerrard et al. (2013) identified a heterozygous c.664C-T transition in exon 6 of the RPL5 gene, resulting in a gln222-to-ter (Q222X) substitution. The patient was diagnosed at age 7 weeks. He had growth retardation, cleft palate, esophageal strictures, eosinophilic esophagitis, triphalangeal thumbs, and hepatic iron overload. He was transfusion-dependent.
Aase, J. M., Smith, D. W. Congenital anemia and triphalangeal thumbs: a new syndrome. J. Pediat. 74: 471-474, 1969. [PubMed: 5764780] [Full Text: https://doi.org/10.1016/s0022-3476(69)80208-8]
Boria, I., Garelli, E., Gazda, H. T., Aspesi, A., Quarello, P., Pavesi, E., Ferrante, D., Meerpohl, J. J., Kartal, M., Da Costa, L., Proust, A., Leblanc, T., and 17 others. The ribosomal basis of Diamond-Blackfan anemia: mutation and database update. Hum. Mutat. 31: 1269-1279, 2010. [PubMed: 20960466] [Full Text: https://doi.org/10.1002/humu.21383]
Dai, M.-S., Shi, D., Jin, Y., Sun, X.-X., Zhang, Y., Grossman, S. R., Lu, H. Regulation of the MDM2-p53 pathway by ribosomal protein L11 involves a post-ubiquitination mechanism. J. Biol. Chem. 281: 24304-24313, 2006. [PubMed: 16803902] [Full Text: https://doi.org/10.1074/jbc.M602596200]
De Keersmaecker, K., Atak, Z. K., Li, N., Vicente, C., Patchett, S., Girardi, T., Gianfelici, V., Geerdens, E., Clappier, E., Porcu, M., Lahortiga, I., Luca, R., and 18 others. Exome sequencing identifies mutation in CNOT3 and ribosomal genes RPL5 and RPL10 in T-cell acute lymphoblastic leukemia. Nature Genet. 45: 186-190, 2013. [PubMed: 23263491] [Full Text: https://doi.org/10.1038/ng.2508]
Frigerio, J.-M., Berthezene, P., Garrido, P., Ortiz, E., Barthellemy, S., Vasseur, S., Sastre, B., Seleznieff, I., Dagorn, J. C., Iovanna, J. L. Analysis of 2166 clones from a human colorectal cancer cDNA library by partial sequencing. Hum. Molec. Genet. 4: 37-43, 1995. [PubMed: 7711732] [Full Text: https://doi.org/10.1093/hmg/4.1.37]
Frigerio, J.-M., Dagorn, J.-C., Iovanna, J. L. Cloning, sequencing and expression of the L5, L21, L27a, L28, S5, S9, S10 and S29 human ribosomal protein mRNAs. Biochim. Biophys. Acta 1262: 64-68, 1995. [PubMed: 7772601] [Full Text: https://doi.org/10.1016/0167-4781(95)00045-i]
Gazda, H. T., Sheen, M. R., Vlachos, A., Choesmel, V., O'Donohue, M.-F., Schneider, H., Darras, N., Hasman, C., Sieff, C. A., Newburger, P. E., Ball, S. E., Niewiadomska, E., and 9 others. Ribosomal protein L5 and L11 mutations are associated with cleft palate and abnormal thumbs in Diamond-Blackfan anemia patients. Am. J. Hum. Genet. 83: 769-780, 2008. [PubMed: 19061985] [Full Text: https://doi.org/10.1016/j.ajhg.2008.11.004]
Gerrard, G., Valganon, M., Foong, H. E., Kasperaviciute, D., Iskander, D., Game, L., Muller, M., Aitman, T. J., Roberts, I., de la Fuente, J., Foroni, L., Karadimitris, A. Target enrichment and high-throughput sequencing of 80 ribosomal protein genes to identify mutations associated with Diamond-Blackfan anaemia. Brit. J. Haemat. 162: 530-536, 2013. [PubMed: 23718193] [Full Text: https://doi.org/10.1111/bjh.12397]
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]
Lin, E., Lin, S.-W., Lin, A. The participation of 5S rRNA in the co-translational formation of a eukaryotic 5S ribonucleoprotein complex. Nucleic Acids Res. 29: 2510-2516, 2001. [PubMed: 11410658] [Full Text: https://doi.org/10.1093/nar/29.12.2510]
Pogue-Geile, K., Geiser, J. R., Shu, M., Miller, C., Wool, I. G., Meisler, A. I., Pipas, J. M. Ribosomal protein genes are overexpressed in colorectal cancer: isolation of a cDNA clone encoding the human S3 ribosomal protein. Molec. Cell. Biol. 11: 3842-3849, 1991. [PubMed: 1712897] [Full Text: https://doi.org/10.1128/mcb.11.8.3842-3849.1991]
Qu, L. H., Nicoloso, M., Michot, B., Azum, M. C., Caizergues-Ferrer, M., Renalier, M. H., Bachellerie, J. P. U21, a novel small nucleolar RNA with a 13 nt. complementarity to 28S rRNA, is encoded in an intron of ribosomal protein L5 gene in chicken and mammals. Nucleic Acids Res. 22: 4073-4081, 1994. [PubMed: 7937132] [Full Text: https://doi.org/10.1093/nar/22.20.4073]