Alternative titles; symbols
HGNC Approved Gene Symbol: RPS4X
Cytogenetic location: Xq13.1 Genomic coordinates (GRCh38): X:72,272,042-72,277,248 (from NCBI)
RPS4Y (470000), a Y-linked gene gene in the human, encodes ribosomal protein S4. RPS4X is a homologous gene on the human X chromosome that lies close to the X-inactivation center (314670) but fails to undergo X inactivation (Fisher et al., 1990).
Wiles et al. (1988) constructed a cDNA library from a mouse-human somatic cell hybrid containing as its only human contribution an X-6 translocation chromosome. From among clones that hybridized most strongly with DNA derived from the hybrid than with a 'mouse only' cell line, they found 1 devoid of repeats. This clone, called SCR10, identified a 1-kb mRNA transcribed from the human X chromosome and mapping to the region Xq13-q13.3 or Xq21.3-q22. It represented an abundantly and ubiquitously expressed gene. A full-length or nearly full-length clone of SCR10, SCAR (RPS4), was isolated and sequenced; the conceptual translation of this sequence indicated a basic protein of 27.5 kD. Sequences homologous to SCAR were detected in primates, rodents, avians, and Xenopus.
Fisher et al. (1990) demonstrated that the RPS4Y and RPS4X proteins differ at 19 of 263 amino acids. Both genes are widely transcribed in human tissues, suggesting that the ribosomes of human males and females are structurally distinct. By transcription analysis, Fisher et al. (1990) found that 'unlike most genes on the X chromosome, RPS4X is not dosage compensated.' RPS4X was the first gene on the long arm of the X chromosome known to escape X inactivation.
Using FISH, Fisher et al. (1990) mapped the RPS4X gene to chromosome Xq13.1. Fisher et al. (1990) noted that RPS4Y maps to a 90-kb segment on the Y chromosome that has been implicated in Turner syndrome. XY gonadal dysgenesis patients with somatic features of Turner syndrome have been found to have deletion of this portion of Yp. The Turner phenotype, or at least its extragonadal component, is probably the result of the presence of 1 rather than 2 copies of a gene or genes common to the X and Y chromosomes ('haploinsufficiency'). Fisher et al. (1990) considered the possibility that haploinsufficiency of the RPS4 genes contributes to the Turner phenotype.
Genetic mapping utilizing interspecific backcrosses and an intron probe derived from the mouse Rps4 gene demonstrated that Rps4 maps close to the Phka locus on the mouse X chromosome and in the vicinity of the X-inactivation center (Hamvas et al. (1991, 1992)). Lafreniere et al. (1993) studied a 2.6-Mb contig of YACs that completely covered the region of the X-inactivation center and physically linked RPS4X, PHKA1, XIST, and DXS128E (an expressed DNA segment of unknown function), as well as a laminin receptor pseudogene (LAMRP4; see 150370). The order of genes was shown to be cen--RPS4X--PHKA1--XIST--DXS128E--tel. The transcriptional orientation of the RPS4X gene was cen--5-prime--3-prime--qter.
Kenmochi et al. (1998) confirmed the mapping assignment of the RPS4X gene to chromosome Xq.
Zinn et al. (1991) found that in the mouse the Rps4 gene is indeed subject to X inactivation. This finding may explain why the phenotypic consequences of X monosomy are less severe in mice than in humans; the X0 mouse is a fertile female.
Watanabe et al. (1993) demonstrated that the RPS4Y and RPS4X ribosomal proteins are interchangeable and provide an essential function: either protein rescued a mutant hamster cell line that was otherwise incapable of growth at modestly elevated temperatures. These findings are consistent with the hypothesis that RPS4 deficiency has a role in Turner syndrome.
Geerkens et al. (1996) concluded that haploinsufficiency of RPS4X cannot be the cause of Turner syndrome because patients with 46,Xi(Xq) karyotype, i.e., isochromosome Xq, cannot be differentiated phenotypically from 45,X Turner syndrome patients but carry 3 copies of the RPS4X gene. In 4 patients with typical manifestations and a nonmosaic chromosome complement of isochromosome Xq, the authors found significantly increased RPS4X mRNA levels.
Watanabe et al. (1991) demonstrated that CCG2, the human gene that complements the temperature-sensitive cell cycle mutant tsBN63, is identical to the SCAR/RPS4X gene.
Omoe and Endo (1996) compared sequences of the X- and Y-linked RPS4 genes from several mammals and showed that these 2 loci diverged prior to the radiation of the placental mammals. Furthermore, the Y-linked homolog is absent in many species, members of which can show the monosomy X phenotype (Turner syndrome in humans). From this the authors concluded that, rather than single RPS4 haploinsufficiency, there may be other genes that contribute to abnormal phenotypes of monosomy X.
Using knockin mice carrying a human BAC containing multiple human genes with different X-chromosome inactivation (XCI) statuses, Peeters et al. (2018) confirmed that RPS4X was a primate-specific escape gene. Analysis with knockin male mice carrying the BAC on their single active X chromosome showed that the integrated BAC retained all necessary elements for functional transcription, and that those human elements were recognized by mice to express RPS4X from the always active X chromosome in males. Analysis with knockin female mice carrying the BAC on their X chromosomes showed that RPS4X was not only expressed from the active X chromosome of female mice, but also that it escaped XCI even when it was integrated into the inactive X chromosome of the females, and that it was expressed with patterns consistent with the corresponding tissues in human. In corroboration of RPS4X being an escape gene, the RPS4X promoter transcribed from the inactive X chromosome of the females was hypomethylated in all tissues, like the RPS4X promoter transcribed from the active X chromosome of the knockin males. Further analysis indicated that the RPS4X BAC likely contained elements that contributed to escape of RPS4X from XCI in the females.
Fisher, E. M. C., Beer-Romero, P., Brown, L. G., Ridley, A., McNeil, J. A., Lawrence, J. B., Willard, H. F., Bieber, F. R., Page, D. C. Homologous ribosomal protein genes on the human X and Y chromosomes: escape from X inactivation and possible implications for Turner syndrome. Cell 63: 1205-1218, 1990. [PubMed: 2124517] [Full Text: https://doi.org/10.1016/0092-8674(90)90416-c]
Geerkens, C., Just, W., Held, K. R., Vogel, W. Ullrich-Turner syndrome is not caused by haploinsufficiency of RPS4X. Hum. Genet. 97: 39-44, 1996. [PubMed: 8557258] [Full Text: https://doi.org/10.1007/BF00218830]
Hamvas, R. M., Brown, S. D., Keer, J. T., Fisher, E. M., Romero, P., Zinn, A., Page, D. The mapping of the locus Rps4 to the X-inactivation region in the mouse. (Abstract) Cytogenet. Cell Genet. 58: 2065-2066, 1991.
Hamvas, R. M. J., Zinn, A., Keer, J. T., Fisher, E. M. C., Beer-Romero, P., Brown, S. D. M., Page, D. C. Rps4 maps near the inactivation center on the mouse X chromosome. Genomics 12: 363-367, 1992. [PubMed: 1740345] [Full Text: https://doi.org/10.1016/0888-7543(92)90386-7]
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]
Lafreniere, R. G., Brown, C. J., Rider, S., Chelly, J., Taillon-Miller, P., Chinault, A. C., Monaco, A. P., Willard, H. F. 2.6 Mb YAC contig of the human X inactivation center region in Xq13: physical linkage of the RPS4X, PHKA1, XIST and DXS128E genes. Hum. Molec. Genet. 2: 1105-1115, 1993. [PubMed: 8401491] [Full Text: https://doi.org/10.1093/hmg/2.8.1105]
Omoe, K., Endo, A. Relationship between the monosomy X phenotype and Y-linked ribosomal protein S4 (Rps4) in several species of mammals: a molecular evolutionary analysis of Rps4 homologs. Genomics 31: 44-50, 1996. [PubMed: 8808278] [Full Text: https://doi.org/10.1006/geno.1996.0007]
Peeters, S. B., Korecki, A. J., Simpson, E. M., Brown, C. J. Human cis-acting elements regulating escape from X-chromosome inactivation function in mouse. Hum. Molec. Genet. 27: 1252-1262, 2018. [PubMed: 29401310] [Full Text: https://doi.org/10.1093/hmg/ddy039]
Watanabe, M., Furuno, N., Goebl, M., Go, M., Miyauchi, K., Sekiguchi, T., Basilico, C., Nishimito, T. Molecular cloning of the human gene, CCG2, that complements the BHK-derived temperature-sensitive cell cycle mutant tsBN63: identity of CCG2 with the human X chromosomal SCAR/RPS4X gene. J. Cell Sci. 100: 35-43, 1991. [PubMed: 1795030] [Full Text: https://doi.org/10.1242/jcs.100.1.35]
Watanabe, M., Zinn, A. R., Page, D. C., Nishimoto, T. Functional equivalence of human X- and Y-encoded isoforms of ribosomal protein S4 consistent with a role in Turner syndrome. Nature Genet. 4: 268-271, 1993. [PubMed: 8358435] [Full Text: https://doi.org/10.1038/ng0793-268]
Wiles, M. V., Alexander, C. M., Goodfellow, P. N. Isolation of an abundantly expressed sequence from the human X chromosome by differential screening. Somat. Cell Molec. Genet. 14: 31-39, 1988. [PubMed: 2829364] [Full Text: https://doi.org/10.1007/BF01535047]
Zinn, A. R., Bressler, S. L., Beer-Romero, P., Adler, D. A., Chapman, V. M., Page, D. C., Disteche, C. M. Inactivation of the Rps4 gene on the mouse X chromosome. Genomics 11: 1097-1101, 1991. Note: Erratum: Genomics 13: 915 only, 1992. [PubMed: 1783379] [Full Text: https://doi.org/10.1016/0888-7543(91)90037-f]