Alternative titles; symbols
HGNC Approved Gene Symbol: RPSA
SNOMEDCT: 205735005, 93292008;
Cytogenetic location: 3p22.1 Genomic coordinates (GRCh38): 3:39,406,720-39,412,542 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 3p22.1 | Asplenia, isolated congenital | 271400 | Autosomal dominant | 3 |
Gehlsen et al. (1988) isolated a receptor for the adhesive basement membrane protein laminin (150290, 150310, 150320) from human glioblastoma cells by affinity chromatography on laminin. These RuGli glioblastoma cells were later shown to be rat cells (Gehlsen et al., 1988). This receptor has a heterodimeric structure similar to that of receptors for other extracellular matrix proteins such as the fibronectin (135620) and vitronectin (193210) receptors. Incorporation of the laminin receptor into lysosomal membranes made it possible for lysosomes to attach to surfaces coated with laminin.
Bignon et al. (1991) cloned 2 cDNAs for the human 67-kD laminin receptor. They found that these clones hybridize to many restriction fragments in Southern blot analyses in the human. The particular patterns were accounted for by the presence of up to 16 and 21 copies of the laminin receptor gene per haploid genome in human and mouse, respectively. In contrast, a single gene copy was found in the chicken.
Yow et al. (1988) cloned a human colon carcinoma cDNA encoding a laminin-binding protein. The cDNA hybridized to a 1.2-kb transcript, the level of which was approximately 9-fold higher in colon carcinoma than in adjacent normal colonic epithelium. The deduced 295-amino acid protein has a highly negatively charged C-terminal segment and lacks consensus sequences for an N-terminal signal sequence, amphipathic alpha-helices, and N-glycosylation sites.
Satoh et al. (1992) cloned cDNAs encoding the 67-kD laminin receptor from both a human lung cell line and a human lung cancer cell line. They demonstrated that the level of the laminin receptor transcript was higher in the lung cancer cell line than in the lung cell line.
Tohgo et al. (1994) found that the amino acid sequence of the rat 40S ribosomal subunit is 99% identical to that of the human 68-kD laminin-binding protein, indicating that the 40S ribosomal subunit is identical to the 68-kD laminin-binding protein.
By fluorescence in situ hybridization, Jackers et al. (1996) localized the LAMR1 gene to chromosome 3p21.3. Kenmochi et al. (1998) mapped the LAMR1 gene, which they called RPSA, to 3p by somatic cell hybrid and radiation hybrid mapping panels.
Bignon et al. (1991) identified laminin receptor pseudogenes on chromosomes 3, 12, 14, and X. The features suggested that the laminin receptor gene belongs to a retroposon family in mammals.
Lafreniere et al. (1993) demonstrated that a laminin receptor pseudogene, which they symbolized LAMRP4, is located at Xq13 in a 2.6-Mb segment that also contains the XIST gene (314670).
The 37-kD precursor of the 67-kD laminin receptor (37LRP) is a polypeptide whose expression is consistently upregulated in aggressive carcinoma. It appears to be a multifunctional protein involved in the translational machinery; it has also been identified as p40 ribosome-associated protein. Jackers et al. (1996) isolated the active 37LRP/p40 human gene. They found that it contains 7 exons. Ribonuclease protection experiments suggested multiple transcription start sites. The promoter area does not bear a TATA box but contains 4 Sp1 sites. The first intron is also GC-rich, containing 5 Sp1 sites. Intron 4 contains a full sequence of the small nucleolar E2 RNA (RNE2; 180646) between nucleotides 4365 and 4516, and intron 3 contains 2 Alu sequences.
Montuori et al. (1999) investigated the expression of integrin laminin receptors in normal thyroid primary cultures; immortalized normal thyroid cells (TAD-2); papillary (NPA), follicular (WRO), and anaplastic (ARO) thyroid tumor cell lines; 7 thyroid tumors (4 papillary and 3 follicular carcinomas); and normal thyroid glands. Despite the presence of several integrin laminin receptors, adhesion of TAD-2, NPA, and ARO cells to immobilized laminin-1 was poor, whereas WRO cells and follicular carcinoma-derived cells displayed a strong adhesion. Indeed, WRO and follicular carcinoma-derived cells showed expression of a nonintegrin laminin receptor, the 67-kD high-affinity laminin receptor (67LR). TAD-2, NPA, and ARO cells as well as nodular goiter, toxic adenoma, follicular adenoma, and papillary carcinoma-derived cells did not express the 67LR. The expression in follicular carcinoma cells of a functional, high-affinity 67LR, together with nonfunctional integrin laminin receptors, could be responsible for the tendency of follicular carcinoma cells to metastasize by mediating stable contacts with basal membranes.
Chen et al. (2002) found that human normal and leukemic T cells produce GNRH2 (602352) and GNRH1 (152760). Exposure of normal or cancerous human or mouse T cells to GNRH2 or GNRH1 triggered de novo gene transcription and cell-surface expression of the laminin receptor, which is involved in cellular adhesion and migration and in tumor invasion and metastasis. GNRH2 or GNRH1 also induced adhesion to laminin and chemotaxis toward SDF1A (600835), and augmented entry in vivo of metastatic T-lymphoma into the spleen and bone marrow. Homing of normal T cells into specific organs was reduced in mice lacking GNRH1. A specific GNRH1 receptor antagonist blocked GNRH1 but not GNRH2-induced effects, which was suggestive of signaling through distinct receptors. Chen et al. (2002) suggested that GNRH2 and GNRH1, secreted from nerves or autocrine or paracrine sources, interact directly with T cells and trigger gene transcription, adhesion, chemotaxis, and homing to specific organs.
Bolze et al. (2013) demonstrated that heterozygous mutations in the RPSA gene cause autosomal dominant isolated congenital asplenia (ICAS; 271400) by haploinsufficiency, revealing an essential role for RPSA in human spleen development. Bolze et al. (2013) identified a nonsense mutation, a frameshift duplication, and 5 different missense mutations (150370.0001-150370.0007). These 7 mutations were not identified in more than 10,000 alleles reported in the 1000 Genomes Project or the NHLBI Exome Sequencing Project databases. The missense mutations affected residues strictly conserved in mammals, vertebrates, and yeast.
Arrhythmogenic right ventricular dysplasia (ARVD; 107970) is a hereditary cardiomyopathy that causes sudden death in the young. Asano et al. (2004) found a line of mice with inherited right ventricular dysplasia (RVD) caused by mutation of the gene laminin receptor-1 (Lamr1). This locus contained an intron-processing retroposon that was transcribed in the mice with RVD. Introduction of a mutated Lamr1 gene into normal mice by breeding or by direct injection caused susceptibility to RVD, which was similar to that seen in the RVD mice. An in vitro study of cardiomyocytes expressing the product of mutated Lamr1 showed early cell death accompanied by alteration of the chromatin architecture. They found that heterochromatin protein-1 (HP1; 604478) bound specifically to mutant Lamr1. HP1 is a dynamic regulator of heterochromatin sites, suggesting that mutant LAMR1 impairs a crucial process of transcriptional regulation. Indeed, mutant Lamr1 caused specific changes to gene expression in cardiomyocytes, as detected by gene chip analysis. Asano et al. (2004) concluded that products of the Lamr1 transposon interact with HP1 to cause degeneration of cardiomyocytes. This mechanism may also contribute to the etiology of human ARVD. They noted that the human LAMR1 gene maps to 3p21 and that a form of ARVD, ARVD5 (604400), maps to 3p23.
In affected members of a Caucasian family from the United States (kindred E) with isolated congenital asplenia (ICAS; 271400), Bolze et al. (2013) identified heterozygosity for a c.25C-T transition in the RPSA gene that resulted in a nonsense mutation, gln9 to ter (Q9X). The mutation segregated in the mother and son and was presumably present in 2 other sibs who had died of overwhelming infection.
In a mother and 2 sons (kindred C) with isolated congenital asplenia (ICAS; 271400), Bolze et al. (2013) identified heterozygosity for a 5-bp duplication in exon 5 of the RPSA gene (c.590_594dup) that resulted in frameshift and premature termination (Pro199SerfsTer25). Cloning and analysis of protein generated from activated T cells from patients showed that less than 10% of the transcripts carried the mutation, which suggested that mutant mRNAs were subject to nonsense-mediated decay. The mother was Caucasian and the father was of Tamil descent from Reunion Island. This family had been reported by Mahlaoui et al. (2011) as family D.
In affected members of 2 families (kindreds D and A) with isolated congenital asplenia (ICAS; 271400), Bolze et al. (2013) detected heterozygosity for a c.538C-G transversion in the RPSA gene that resulted in an arg180-to-gly substitution (R180G). Haplotype analysis indicated that the mutation arose independently in each kindred. In kindred A, affected individuals occurred in 3 generations.
In a Caucasian individual from Sweden (kindred T) with isolated congenital asplenia (ICAS; 271400), Bolze et al. (2013) identified heterozygosity for a 538C-T transition in the RPSA gene that resulted in an arg180-to-trp substitution (R180W). Since neither parent carried the mutation and the patient had 3 unaffected sibs, the mutation was presumed to have arisen de novo.
In a family of Congolese origin (kindred B) with 3 affected members with isolated congenital asplenia (ICAS; 271400), Bolze et al. (2013) identified a heterozygous c.556C-T transition in the RPSA gene that resulted in an arg186-to-cys substitution (R186C). This family had been reported by Mahlaoui et al. (2011) as family E and had been reported by Koss et al. (2012) as having a causative mutation in the NKX2-5 gene (600584.0024). The RPSA mutation segregated with the disease in a father and 2 sons, one deceased; 3 other deceased sibs were probably affected. Koss et al. (2012) presented a case report of this family. Three children died of fulminant infection within the first year of life; they were not further studied. A fourth child died of sepsis at age 23 months. Postmortem examination of this child showed asplenia with normal heart and visceral placement, and mutation analysis identified the P236H mutation. The fifth child and the father, who both carried the mutation, were found to have ICAS; the child was placed on prophylaxis, whereas the father did not have a history of infections, suggesting incomplete penetrance. Studies in mouse embryos and cellular studies of splenic mesenchymal cells demonstrated a pivotal role for the NKX2-5 gene in spleen development.
In 2 affected children with isolated congenital asplenia (ICAS; 271400) from a Caucasian French family (kindred F), Bolze et al. (2013) identified heterozygosity for a c.161C-A transversion in the RPSA gene that resulted in a thr54-to-asn substitution (T54N). Since neither parent was found to carry the mutation, inheritance was attributed to germline mosaicism. This family had been reported by Mahlaoui et al. (2011) as family B, and by Ferlicot et al. (1997).
In an individual of French descent (kindred O) with isolated congenital asplenia (ICAS; 271400), Bolze et al. (2013) identified heterozygosity for a c.172C-T transition in the RPSA gene that resulted in a leu58-to-phe substitution (L58F). The mutation apparently arose de novo.
Asano, Y., Takashima, S., Asakura, M., Shintani, Y., Liao, Y., Minamino, T., Asanuma, H., Sanada, S., Kim, J., Ogai, A., Fukushima, T., Oikawa, Y., Okazaki, Y., Kaneda, Y., Sato, M., Miyazaki, J., Kitamura, S., Tomoike, H., Kitakaze, M., Hori, M. Lamr1 functional retroposon causes right ventricular dysplasia in mice. Nature Genet. 36: 123-130, 2004. [PubMed: 14730304] [Full Text: https://doi.org/10.1038/ng1294]
Bignon, C., Roux-Dosseto, M., Zeigler, M. E., Mattei, M.-G., Lissitzky, J.-C., Wicha, M. S., Martin, P.-M. Genomic analysis of the 67-kDa laminin receptor in normal and pathological tissues: circumstantial evidence for retroposon features. Genomics 10: 481-485, 1991. [PubMed: 1649122] [Full Text: https://doi.org/10.1016/0888-7543(91)90336-d]
Bolze, A., Mahlaoui, N., Byun, M., Turner, B., Trede, N., Ellis, S. R., Abhyankar, A., Itan, Y., Patin, E., Brebner, S., Sackstein, P., Puel, A., and 20 others. Ribosomal protein SA haploinsufficiency in humans with isolated congenital asplenia. Science 340: 976-978, 2013. [PubMed: 23579497] [Full Text: https://doi.org/10.1126/science.1234864]
Chen, A., Ganor, Y., Rahimipour, S., Ben-Aroya, N., Koch, Y., Levite, M. The neuropeptides GnRH-II and GnRH-I are produced by human T cells and trigger laminin receptor gene expression, adhesion, chemotaxis and homing to specific organs. Nature Med. 8: 1421-1426, 2002. [PubMed: 12447356] [Full Text: https://doi.org/10.1038/nm1202-801]
Ferlicot, S., Emile, J.-F., Le Bris, J.-L., Cheron, G., Brousse, N. L'asplenie congenitale: un deficit immunitaire de l'enfant de decouverte souvent trop tardive. Ann. Path. 17: 44-46, 1997. [PubMed: 9162158]
Gehlsen, K. R., Dillner, L., Engvall, E., Ruoslahti, E. The human laminin receptor is a member of the integrin family of cell adhesion receptors. Science 241: 1228-1229, 1988. Note: Erratum: Science 245: 342-343, 1989. Also see Erratum: J. Cell. Biol. 108: following 2546, 1989. [PubMed: 2970671] [Full Text: https://doi.org/10.1126/science.2970671]
Jackers, P., Minoletti, F., Belotti, D., Clausse, N., Sozzi, G., Sobel, M. E., Castronovo, V. Isolation from a multigene family of the active human gene of the metastasis-associated multifunctional protein 37LRP/p40 at chromosome 3p21.3. Oncogene 13: 495-503, 1996. Note: Erratum: Oncogene 14: 627 only, 1997. [PubMed: 8760291]
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]
Koss, M., Bolze, A., Brendolan, A., Saggese, M., Capellini, T. D., Bojilova, E., Boisson, B., Prall, O. W. J., Elliott, D. A., Solloway, M., Lenti, E., Hidaka, C., Chang, C.-P., Mahlaoui, N., Harvey, R. P., Casanova, J.-L., Selleri, L. Congenital asplenia in mice and humans with mutations in a Pbx/Nkx2-5/p15 module. Dev. Cell 22: 913-926, 2012. [PubMed: 22560297] [Full Text: https://doi.org/10.1016/j.devcel.2012.02.009]
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]
Mahlaoui, N., Minard-Colin, V., Picard, C., Bolze, A., Ku, C.-L., Tournilhac, O., Gilbert-Dussardier, B., Pautard, B., Durand, P., Devictor, D., Lachassinne, E., Guillois, B., Morin, M., Gouraud, F., Valensi, F., Fischer, A., Puel, A., Abel, L., Bonnet, D., Casanova, J.-L. Isolated congenital asplenia: a French nationwide retrospective survey of 20 cases. J. Pediat. 158: 142-148, 2011. [PubMed: 20846672] [Full Text: https://doi.org/10.1016/j.jpeds.2010.07.027]
Montuori, N., Muller, F., De Riu, S., Fenzi, G., Sobel, M. E., Rossi, G., Vitale, M. Laminin receptors in differentiated thyroid tumors: restricted expression of the 67-kilodalton laminin receptor in follicular carcinoma cells. J. Clin. Endocr. Metab. 84: 2086-2092, 1999. [PubMed: 10372715] [Full Text: https://doi.org/10.1210/jcem.84.6.5721]
Satoh, K., Narumi, K., Sakai, T., Abe, T., Kikuchi, T., Matsushima, K., Sindoh, S., Motomiya, M. Cloning of 67-kDa laminin receptor cDNA and gene expression in normal and malignant cell lines of the human lung. Cancer Lett. 62: 199-203, 1992. [PubMed: 1534510] [Full Text: https://doi.org/10.1016/0304-3835(92)90096-e]
Tohgo, A., Takasawa, S., Munakata, H., Yonekura, H., Hayashi, N., Okamoto, H. Structural determination and characterization of a 40 kDa protein isolated from rat 40 S ribosomal subunit. FEBS Lett. 340: 133-138, 1994. [PubMed: 8119397] [Full Text: https://doi.org/10.1016/0014-5793(94)80188-6]
Yow, H. K., Wong, J. M., Chen, H. S., Lee, C. G., Davis, S., Steele, G. D., Jr., Chen, L. B. Increased mRNA expression of a laminin-binding protein in human colon carcinoma: complete sequence of a full-length cDNA encoding the protein. Proc. Nat. Acad. Sci. 85: 6394-6398, 1988. Note: Erratum: Proc. Nat. Acad. Sci. 86: 7032 only, 1989. [PubMed: 2970639] [Full Text: https://doi.org/10.1073/pnas.85.17.6394]