Alternative titles; symbols
HGNC Approved Gene Symbol: CAPRIN1
Cytogenetic location: 11p13 Genomic coordinates (GRCh38): 11:34,051,731-34,102,610 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 11p13 | Neurodegeneration, childhood-onset, with cerebellar ataxia and cognitive decline | 620636 | Autosomal dominant | 3 |
| Neurodevelopmental disorder with language impairment, autism, and attention deficit-hyperactivity disorder | 620782 | Autosomal dominant | 3 |
The CAPRIN1 gene encodes a ubiquitously expressed RNA-binding protein (RBP) that regulates the transport and translation of mRNAs of synaptic proteins in the brain. It is also a component of stress granules, which are cytoplasmic assemblies of RBPs and stalled mRNAs that form under stress conditions (summary by Delle Vedove et al., 2022).
The apical and basolateral borders of epithelial cells are distinguished by their different protein and lipid components. The sorting of newly synthesized membrane constituents to the appropriate region of the cell is accomplished either in the trans-Golgi network or by transcytosis, the selected transport of proteins to the appropriate surface. Transcytosis also is involved in the internalization of proteins and ligands at one surface and their transport to another. Ellis and Luzio (1995) identified a protein which undergoes this process by raising antibodies against apical and basolateral membrane fractions prepared from the human intestinal cell line Caco-2 and treated with phosphatidylinositol-specific phospholipase C, an enzyme that cleaves glycosylphosphatidylinositol (GPI) linkages. The antibodies were then used to isolate cDNAs from a human colon carcinoma expression vector library. A composite cDNA sequence was determined that predicts a protein of 649 amino acids that migrates as a 137-kD homodimer; Ellis and Luzio (1995) designated the protein p137(GPI). The protein contains 3 distinct domains. The amino-terminal 275 residues contain several potential alpha helices, the middle region contains proline and glutamine-rich repeats, and residues 469 to 601 contain a potential GPI anchor site. Northern blot analysis showed 3.4- and 2.7-kb transcripts in all tissues examined; 5.3- and 2.0-kb mRNAs were also observed in testis. Ellis and Luzio (1995) showed that the protein was present at nearly equal amounts in both the apical and basolateral membranes of Caco-2 cells and that the protein appeared first at the basolateral side.
Gessler et al. (1996) reported that mouse cDNA clones corresponding to the amino-terminal end of the protein showed that the human and mouse genes share greater than 97% sequence identity.
Using immunoblot, flow cytometric, and immunofluorescence microscopy analyses, Grill et al. (2004) identified a 116-kD phosphorylated protein, caprin-1, that was expressed in the cytoplasm of activated mouse T and B cells and showed highest expression in mouse thymus and spleen. Database and sequence analyses indicated that caprin-1 is identical to p137GPI, but Grill et al. (2004) noted that the original p137GPI sequence contains significant errors. Most notably, the authentic protein does not have a GPI anchor site or a signal peptide. The 709-amino acid human caprin-1 protein shares 96% and 68% identity with the mouse and frog proteins, respectively. It contains 2 highly conserved regions, termed homology region-1 (HR1) and HR2, that are also present in a paralog, caprin-2 (CAPRIN2; 610375).
By immunoblot analysis of mouse tissues, Shiina and Tokunaga (2010) found that Caprin1, which they called Rng105, was primarily expressed in embryonic brain. In contrast, its paralog, Rng140 (Caprin2), was expressed only in adult mouse brain. Immunofluorescence analysis showed that Rng140 and Rng105 localized to distinct RNA granules in both cultured cells and rat neuronal dendrites.
Using NMR spectroscopy of minimal condensates formed from the C-terminal disordered regions of 2 interacting translational regulators, FMRP (309550) and CAPRIN1, Kim et al. (2019) observed interactions involving arginine-rich and aromatic-rich regions. Kim et al. (2019) found that different FMRP serine/threonine and CAPRIN1 tyrosine phosphorylation patterns controlled phase separation propensity with RNA, including subcompartmentalization, and tuned deadenylation and translation rates in vitro. Kim et al. (2019) concluded that the resulting evidence for residue-specific interactions underlying co-phase separation, phosphorylation-modulated condensate architecture, and enzymatic activity within condensates had implications for how the integration of signaling pathways controls RNA processing and translation.
The CAPRIN1 gene is highly expressed in the human and murine central nervous system, in particular in the cortex and cerebellum (summary by Delle Vedove et al., 2022).
Wang et al. (2005) found that deletion of caprin-1 in a chicken B-cell line resulted in a markedly reduced proliferation rate. They generated chicken B cells deficient in caprin-1 and complemented with human caprin-1 and showed that suppression of the human gene caused slowing of the proliferation rate due to prolongation of the G1 phase of the cell cycle.
Using bioinformatics and molecular biologic approaches, Kaddar et al. (2009) identified CAPRIN1 as a target of microRNA-16 (MIR16; see 609704). Luciferase analysis demonstrated that MIR16 interacted with the 3-prime UTRs of CAPRIN1, HMGA1 (600701), and CCNE1 (123837) and that it downregulated expression of these proteins, which are involved in cell proliferation, in cancer cell lines.
Shiina and Tokunaga (2010) reported that rat Rng140 and Rng105 both bound to mRNA, inhibited translation, and induced formation of RNA granules. Knockdown of either protein in cultured mouse neurons resulted in reduced dendrite length and spine density, and there was no compensatory rescue activity of one protein for the other.
Stress granules are cytoplasmic foci composed of stalled translation preinitiation complexes induced by environmental stress stimuli, including viral infection. Since viruses depend on host translational machinery for propagation, stress-induced translational arrest is important in host antiviral defense. Katoh et al. (2013) found that Japanese encephalitis virus (JEV) core protein inhibited stress granule formation. Affinity capture mass spectrometry analysis showed that JEV core protein bound CAPRIN1. Katoh et al. (2013) proposed that JEV core protein circumvents translational shutoff by inhibiting stress granule formation through an interaction with CAPRIN1.
Grill et al. (2004) determined that the caprin-1 gene contains at least 19 exons.
Gessler et al. (1996) mapped the M11S1 gene to chromosome 11p13 by virtue of their studies of CpG islands in contigs from the region. The gene, which is adjacent to a CpG island, maps about 300 kb telomeric of CAT (115500) and 200 kb centromeric to the LIM-domain only 2 gene (180385). The order of transcription is telomere to centromere.
Childhood-Onset Neurodegeneration With Cerebellar Ataxia And Cognitive Decline
In 2 unrelated patients with childhood-onset neurodegeneration with cerebellar ataxia and cognitive decline (CONDCAC; 620636), Delle Vedove et al. (2022) identified the same de novo heterozygous missense mutation in the CAPRIN1 gene (P512L; 601178.0001). The mutation, which was found by trio-based exome sequencing, was not present in the gnomAD database. In vitro studies in HEK293 and SH-SY5Y cells transfected with the mutation showed that the P512L mutant protein formed insoluble ubiquitinated aggregates that stained for SQSTM1 (601530) and sequestered proteins associated with neurodegenerative disorders, including ATXN2 (601517), GEMIN5 (607005), SNRNP200 (601664), and SNCA (163890). Overall, the findings were consistent with a gain-of-function effect. In a note added in proof, Delle Vedove et al. (2022) stated that they were notified by Gene Matcher of a 14-year-old girl with an identical phenotype and the same de novo CAPRIN1 mutation.
Neurodevelopmental Disorder With Language Impairment, Autism, And Attention Deficit-Hyperactivity Disorder
In 10 unrelated probands with neurodevelopmental disorder with language impairment, autism, and attention deficit-hyperactivity disorder (NEDLAAD; 620782), Pavinato et al. (2023) identified heterozygous putative loss-of-function mutations in the CAPRIN1 gene (see, e.g., 601178.0002-601178.0005). The mutations, which were found by exome sequencing, were not present in the gnomAD database. Almost all mutations occurred de novo, but 1 was inherited from an unaffected mother and another was inherited from a mildly affected father. There were 2 splice site mutations, 2 frameshifts, and 6 nonsense mutations, all predicted to result in CAPRIN1 haploinsufficiency. Western blot analysis of fibroblasts or lymphocytes derived from 4 unrelated patients (2 with splice site mutations and 2 with nonsense mutations) showed about a 50% decrease in CAPRIN1 protein levels, consistent with haploinsufficiency. Human induced pluripotent stem cells (hiPSC) haploinsufficient for CAPRIN1 (CAPRIN1+/-) that were differentiated into cortical neurons showed abnormal neuronal organization and reduced neurite and dendrite length compared to controls. The mutant cells also showed progressive degeneration of neuronal processes, neuronal degeneration, increased calcium signaling, and increased reactive oxygen species (ROS). Haploinsufficient cells had increased global mRNA translation, reduced firing activity, and decreased burst synchronization compared to controls. Pavinato et al. (2023) concluded that CAPRIN1 haploinsufficiency causes abnormal neuronal morphogenesis and function, resulting in a neurodevelopmental disorder.
In 2 unrelated patients with childhood-onset neurodegeneration with cerebellar ataxia and cognitive decline (CONDCAC; 620636), Delle Vedove et al. (2022) identified the same de novo heterozygous c.1535C-T transition (c.1535C-T, NM_005898.5) in exon 14 of the CAPRIN1 gene, resulting in a pro512-to-leu (P512L) substitution at a conserved residue near the prion-like domain (PrLD). The mutation, which was found by trio-based exome sequencing, was not present in the gnomAD database. In vitro studies in HEK293 and SH-SY5Y cells transfected with the mutation showed that the P512L mutant protein formed insoluble ubiquitinated aggregates that stained for SQSTM1 (601530) and sequestered proteins associated with neurodegenerative disorders, including ATXN2, GEMIN5, SNRNP200, and SNCA. Cortical neurons carrying the mutation, generated by CRISPR/Cas9 genome editing of induced pluripotent stem cells (iPSC), did not display protein aggregates, but they had reduced neuronal activity in electrophysiologic studies and showed altered stress granule dynamics. The mutation did not impair CAPRIN1 dimerization, but resulted in an expanded conformation of the protein. CAPRIN1 P521L aggregation was strongly enhanced by RNA in vitro. The findings were consistent with a gain-of-function effect. In a note added in proof, Delle Vedove et al. (2022) stated that they were notified by Gene Matcher of a 14-year-old girl with an identical phenotype and the same de novo CAPRIN1 mutation.
In an 8-year-old boy (P3) with neurodevelopmental disorder with language impairment, autism, and attention deficit-hyperactivity disorder (NEDLAAD; 620782), Pavinato et al. (2023) identified a de novo heterozygous c.879G-A transition (c.879G-A, NM_005898.5) at the last base of exon 8 of the CAPRIN1 gene. The mutation, which was found by trio-based exome sequencing, was not present in the gnomAD database. Analysis of cDNA showed that the variant resulted in the skipping of exon 8 with the loss of 53 nucleotides and an out-of-frame protein. The variant underwent nonsense-mediated mRNA decay and patient cells showed reduced CAPRIN1 protein levels, consistent with haploinsufficiency. The patient had autism spectrum disorder, poor language abilities, dysmorphic features, and mild unilateral hearing loss. He attended a school with a support teacher.
In a 17-year-old girl (P4) with neurodevelopmental disorder with language impairment, autism, and attention deficit-hyperactivity disorder (NEDLAAD; 620782), Pavinato et al. (2023) identified a de novo c.892C-T transition (c.892C-T, NM_005898.5) in exon 9 of the CAPRIN1 gene, resulting in a gln298-to-ter (Q298X) substitution. The mutation, which was found by exome sequencing, was not present in the gnomAD database. Functional studies of the variant and studies of patient cells were not performed, but it was predicted to result in CAPRIN1 haploinsufficiency. The patient had ADHD, high-functioning autism, dysmorphic features, and normal range IQ.
In a 7-year-old boy (P8) with neurodevelopmental disorder with language impairment, autism, and attention deficit-hyperactivity disorder (NEDLAAD; 620782), Pavinato et al. (2023) identified a de novo heterozygous c.1195C-T transition (c.1195C-T, NM_005898.5) in exon 11 of the CAPRIN1 gene, resulting in a gln399-to-ter (Q399X) substitution. The mutation, which was found by exome sequencing, was not present in the gnomAD database. Patient fibroblasts showed decreased protein levels, consistent with CAPRIN1 haploinsufficiency. The patient had ASD, ADHD, poor language, and gastrointestinal issues, but did not have intellectual disability or seizures.
In a 10-year-old girl (P12) with neurodevelopmental disorder with language impairment, autism, and attention deficit-hyperactivity disorder (NEDLAAD; 620782), Pavinato et al. (2023) identified a de novo heterozygous c.1744C-T transition (c.1744C-T, NM_005898.5) in exon 16 of the CAPRIN1 gene, resulting in a gln582-to-ter (Q582X) substitution. The mutation, which was found by exome sequencing, was not present in the gnomAD database. Patient fibroblasts showed decreased protein levels, consistent with CAPRIN1 haploinsufficiency. The patient had severe ADHD, profoundly impaired intellectual development, absent speech, seizures, and hyperkinetic movements.
Delle Vedove, A., Natarajan, J., Zanni, G., Eckenweiler, M., Muinos-Buhl, A., Storbeck, M., Guillen Boixet, J., Barresi, S., Pizzi, S., Holker, I., Korber, F., Franzmann, T. M., Bertini, E. S., Kirschner, J., Alberti, S., Tartaglia, M., Wirth, B. CAPRIN1P512L causes aberrant protein aggregation and associates with early-onset ataxia. Cell. Molec. Life Sci. 79: 526, 2022. [PubMed: 36136249] [Full Text: https://doi.org/10.1007/s00018-022-04544-3]
Ellis, J. A., Luzio, J. P. Identification and characterization of a novel protein (p137) which transcytoses bidirectionally in Caco-2 cells. J. Biol. Chem. 270: 20717-20723, 1995. [PubMed: 7657653] [Full Text: https://doi.org/10.1074/jbc.270.35.20717]
Gessler, M., Klamt, B., Tsaoussidou, S., Ellis, J. A., Luzio, J. P. The gene encoding the GPI-anchored membrane protein p137(GPI) (M11S1) maps to human chromosome 11p13 and is highly conserved in the mouse. Genomics 32: 169-170, 1996. [PubMed: 8786113] [Full Text: https://doi.org/10.1006/geno.1996.0099]
Grill, B., Wilson, G. M., Zhang, K.-X., Wang, B., Doyonnas, R., Quadroni, M., Schrader, J. W. Activation/division of lymphocytes results in increased levels of cytoplasmic activation/proliferation-associated protein-1: prototype of a new family of proteins. J. Immun. 172: 2389-2400, 2004. [PubMed: 14764709] [Full Text: https://doi.org/10.4049/jimmunol.172.4.2389]
Kaddar, T., Rouault, J.-P., Chien, W. W., Chebel, A., Gadoux, M., Salles, G., Ffrench, M., Magaud, J.-P. Two new miR-16 targets: caprin-1 and HMGA1, proteins implicated in cell proliferation. Biol. Cell 101: 511-524, 2009. [PubMed: 19250063] [Full Text: https://doi.org/10.1042/BC20080213]
Katoh, H., Okamoto, T., Fukuhara, T., Kambara, H., Morita, E., Mori, Y., Kamitani, W., Matsuura, Y. Japanese encephalitis virus core protein inhibits stress granule formation through an interaction with caprin-1 and facilitates viral propagation. J. Virol. 87: 489-502, 2013. [PubMed: 23097442] [Full Text: https://doi.org/10.1128/JVI.02186-12]
Kim, T. H., Tsang, B., Vernon, R. M., Sonenberg, N., Kay, L. E., Forman-Kay, J. D. Phospho-dependent phase separation of FMRP and CAPRIN1 recapitulates regulation of translation and deadenylation. Science 365: 825-829, 2019. [PubMed: 31439799] [Full Text: https://doi.org/10.1126/science.aax4240]
Pavinato, L., Delle Vedove, A., Carli, D., Ferrero, M., Carestiato, S., Howe, J. L., Agolini, E., Coviello, D. A., van de Laar, I., Au, P. Y. B., Di Gregorio, E., Fabbiani, A., and 22 others. CAPRIN1 haploinsufficiency causes a neurodevelopmental disorder with language impairment, ADHD and ASD. Brain 146: 534-548, 2023. [PubMed: 35979925] [Full Text: https://doi.org/10.1093/brain/awac278]
Shiina, N., Tokunaga, M. RNA granule protein 140 (RNG140), a paralog of RNG105 localized to distinct RNA granules in neuronal dendrites in the adult vertebrate brain. J. Biol. Chem. 285: 24260-24269, 2010. [PubMed: 20516077] [Full Text: https://doi.org/10.1074/jbc.M110.108944]
Wang, B., David, M. D., Schrader, J. W. Absence of Caprin-1 results in defects in cellular proliferation. J. Immun. 175: 4274-4282, 2005. [PubMed: 16177067] [Full Text: https://doi.org/10.4049/jimmunol.175.7.4274]