HGNC Approved Gene Symbol: RPL11
Cytogenetic location: 1p36.11 Genomic coordinates (GRCh38) : 1:23,691,779-23,696,835 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1p36.11 | Diamond-Blackfan anemia 7 | 612562 | Autosomal dominant | 3 |
The mammalian ribosome is composed of 4 RNA species (see 180450) and approximately 80 different proteins (see 180466), including RPL11 (Kenmochi et al., 1998).
Using PCR, Mishin et al. (1995) isolated a human placenta cDNA encoding RPL11. The deduced RPL11 protein has 178 amino acids.
Boria et al. (2010) stated that the RPL11 gene contains 6 exons spanning 4.6 kb.
By somatic cell hybrid and radiation hybrid mapping analyses, Kenmochi et al. (1998) mapped the human RPL11 gene to chromosome 1p. Graphodatsky et al. (1999) localized the RPL11 gene to chromosome 1p36.1-p35 using FISH.
Impeding ribosomal biogenesis generates ribosomal stress that activates p53 (TP53; 191170) to stop cell growth. Dai et al. (2006) stated that ribosomal proteins L5 (RPL5; 603634), L11, 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 MDM2 autoubiquitination and MDM2-mediated ubiquitination of p53 in human cell lines. In contrast, L11 increased the cellular level of ubiquitinated MDM2 and stabilized p53. These effects required the autoubiquitination activity of MDM2 and involved direct binding of L11 to MDM2 via its central MDM2-binding domain.
Fumagalli et al. (2009) showed that RPL11-mediated p53 induction in human cell lines was a general response to inhibition of 40S or 60S ribosome biogenesis and did not require nucleolar disruption. Inhibition of 40S ribosome biogenesis led to increased ribosome-free RPL11 due to derepression of the polypyrimidine tract at its 5-prime transcriptional start site (the 5-prime TOP), followed by increased RPL11 mRNA translation. Fumagalli et al. (2009) hypothesized that impairment of the assembly of RPL11 into nascent 60S ribosomes allows excess RPL11 to inhibit MDM2 and stabilize p53. In contrast, when 40S ribosome biogenesis is impaired, 60S ribosome biogenesis continues, leading to translational upregulation of mRNAs with 5-prime TOPs, including that for RPL11, despite inhibition of global protein synthesis.
Sasaki et al. (2011) found that conditional deletion of Pict1 (GLTSCR2; 605691) expression in mouse embryonic stem (ES) cells inhibited cell growth due to cell cycle arrest and enhanced apoptosis. Mass spectrometric analysis of peptides that immunoprecipitated with epitope-tagged PICT1 in transfected 293T cells showed that PICT1 interacted with RPL11. Knockdown of Pict1 in mouse ES cells resulted in translocation of Rpl11 from the nucleolus to the nucleoplasm, permitting its interaction with Mdm2 and inhibition of p53 ubiquitination. Sasaki et al. (2011) concluded that PICT1 is a potent regulator of the MDM2-p53 pathway.
Ebina et al. (2013) noted that most L11 is neddylated and localizes in nucleolus. In response to nucleolar stress, L11 is deneddylated and relocates to the nucleoplasm, leading to activation of the p53 pathway. The authors found that expression of MYEOV2 (COPS9; 619349) blocked L11 neddylation, which was mediated NEDP1 (SENP8; 608659) independently of MYEOV2. Consequently, MYEOV2 suppressed translocation of L11 into nucleolus from nucleoplasm, upregulating p53 transcriptional activity and making cells sensitive to a variety of stresses.
Gazda et al. (2008) screened 196 probands with Diamond-Blackfan anemia (see DBA7, 612562) for mutations in 25 genes encoding ribosomal proteins and identified 11 different mutations in the RPL11 gene in 13 probands and 5 additional family members (see, e.g., 604175.0001-604175.0004). 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 heterozygous truncating mutations in the RPL11 gene (see, e.g., 604175.0005-604175.0006) in 3 of 19 patients with DBA who were screened for mutations in 80 ribosomal protein genes.
In a female patient in whom Diamond-Blackfan anemia (DBA7; 612562) was diagnosed at 2 months of age, who also had triphalangeal thumbs, Gazda et al. (2008) identified heterozygosity for a de novo 223C-T transition in exon 3 of the RPL11 gene, resulting in an arg75-to-ter (R75X) substitution. The mutation was not found in her unaffected parents or in at least 150 controls.
In a female patient in whom Diamond-Blackfan anemia (DBA7; 612562) was diagnosed at 9 months of age, who also had triphalangeal thumbs, ventricular septal defect, and a narrow pulmonary artery, Gazda et al. (2008) identified heterozygosity for a 2-bp deletion (60delCT) in exon 2 of the RPL11 gene, resulting in a frameshift causing a termination sequence at codon 53. The mutation was also identified in her affected mother and grandmother, who both had associated triphalangeal thumbs, but was not found in at least 150 controls.
In a female patient in whom Diamond-Blackfan anemia (DBA7; 612562) was diagnosed at 2 months of age and who had no associated malformations, Gazda et al. (2008) identified heterozygosity for a 3-bp deletion (482delAGG) in exon 5 of the RPL11 gene, resulting in deletion of glu161 (E161del). The mutation was identified in her affected mother, who also had no associated malformations, but was not found in at least 150 controls.
In 2 male patients with Diamond-Blackfan anemia (DBA7; 612562), who both had associated malformations, Gazda et al. (2008) identified heterozygosity for a G-A transition at the acceptor splice site in intron 2 (IVS2AS-1G-A) of the RPL11 gene. Associated features in 1 patient included a flat thenar muscle and small jaw, whereas the other patient had tetralogy of Fallot and bilateral grade 3 vesicoureteral reflux.
In a 7-year-old Caucasian boy with Diamond-Blackfan anemia-7 (DBA7; 612562), Gerrard et al. (2013) identified a heterozygous 2-bp deletion (c.475_476delAA) in exon 5 of the RPL11 gene, resulting in a frameshift and premature termination in exon 6. The patient was diagnosed at birth and had elevated erythrocyte adenosine deaminase. He also had patent ductus arteriosus, hypoplastic thumbs, recurrent chest infections, and vitamin D deficiency. The disorder was steroid-responsive.
In a 5-year-old Indian girl (patient CZ02) with Diamond-Blackfan anemia (DBA7; 612562), Gerrard et al. (2013) identified a heterozygous 1-bp deletion (c.203delT) in exon 3 of the RPL11 gene, resulting in a frameshift and premature termination in exon 3. The patient was diagnosed at age 3 months. She had growth retardation and recurrent infections, and was transfusion-dependent.
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]
Ebina, M., Tsuruta, F., Katoh, M. C., Kigoshi, Y., Someya, A., Chiba, T. Myeloma overexpressed 2 (Myeov2) regulates L11 subnuclear localization through Nedd8 modification. PLoS One 8: e65285, 2013. [PubMed: 23776465] [Full Text: https://doi.org/10.1371/journal.pone.0065285]
Fumagalli, S., Di Cara, A., Neb-Gulati, A., Natt, F., Schwemberger, S., Hall, J., Babcock, G. F., Bernardi, R., Pandolfi, P. P., Thomas, G. Absence of nucleolar disruption after impairment of 40S ribosome biogenesis reveals an rpL11-translation-dependent mechanism of p53 induction. Nature Cell Biol. 11: 501-508, 2009. [PubMed: 19287375] [Full Text: https://doi.org/10.1038/ncb1858]
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]
Graphodatsky, A. S., Vorobieva, N. V., Filipenko, M. L., Voronina, E. V., Frengen, E., Prydz, H. Assignment of the L11 ribosomal protein gene (RPL11) to human chromosome 1p36.1-p35 by in situ hybridization. Cytogenet. Cell Genet. 84: 97-98, 1999. [PubMed: 10343117] [Full Text: https://doi.org/10.1159/000015228]
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]
Mishin, V. P., Filipenko, M. L., Muravlev, A. I., Karpova, G. G., Mertvetsov, N. P. Cloning and determination of the primary structure of DNA complementary to the mRNA of human ribosomal protein L11. Bioorg. Khim. 21: 158-160, 1995. Note: Article in Russian. [PubMed: 7748210]
Sasaki, M., Kawahara, K., Nishio, M., Mimori, K., Kogo, R., Hamada, K., Itoh, B., Wang, J., Komatsu, Y., Yang, Y. R., Hikasa, H., Horie, Y., and 11 others. Regulation of the MDM2-P53 pathway and tumor growth by PICT1 via nucleolar RPL11. Nature Med. 17: 944-951, 2011. [PubMed: 21804542] [Full Text: https://doi.org/10.1038/nm.2392]