Alternative titles; symbols
HGNC Approved Gene Symbol: SRRM2
Cytogenetic location: 16p13.3 Genomic coordinates (GRCh38) : 16:2,752,638-2,771,412 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 16p13.3 | Intellectual developmental disorder, autosomal dominant 72 | 620439 | Autosomal dominant | 3 |
The 300-kD nuclear matrix antigen SRM300 forms a complex with the 160-kD serine/arginine (SR)-related nuclear matrix protein SRM160 (605975) known as the SRM160/300 splicing coactivator. This complex functions in splicing by promoting critical interactions between splicing factors bound to pre-mRNA, including snRNPs and SR family proteins (summary by Blencowe et al., 2000).
By biochemical purification, micropeptide sequence analysis, EST database searching, and screening a monocytoid cDNA library, Blencowe et al. (2000) isolated a cDNA encoding SRM300. Like SRM160, the deduced 2,296-amino acid SRM300 protein is rich in serine (S), arginine (R), and proline (P), has numerous SR dipeptides and 2 long polyserine domains, and lacks an RNA recognition domain. A portion of the SRM300 protein is identical to a partial protein, KIAA0324, identified by Nagase et al. (1997). By RT-PCR analysis, Nagase et al. (1997) detected ubiquitous expression of KIAA0324. Using immunoblot and immunoprecipitation analyses and confocal microscopy, Blencowe et al. (2000) confirmed that SRM300 associates with SRM160 and pre-mRNA and is localized in nuclear speckles. Reconstitution of SRM160/SRM300-depleted splicing reactions with recombinant SRM160 restored splicing activity, suggesting that SRM160 is the more important component of the complex.
By screening a cDNA library for RNA ligands, Sawada et al. (2000) identified a cDNA encoding SRM300, which they termed SRL300. The deduced 2,752-amino acid protein has multiple R, S, and P residues, numerous phosphorylation sites, and a predicted molecular mass of 300 kD, suggesting that it may be the full-length protein. Immunoblot analysis detected GST fusion proteins of greater than 300 kD in human and rat cells. Northern blot analysis revealed expression of a 9.0- to 10.0-kb SRL300 transcript in all tissues and cell lines tested.
By yeast 2-hybrid analysis of HeLa cells, followed by sequence analysis, Zimowska et al. (2003) found that epitope-tagged human PNN (603154) interacted with the SR-rich proteins SRP75 (SRSF4; 601940), SRM300, and SRRP130 (PNISR; 616653). The 4 proteins colocalized in the nucleus of HCE-T human corneal epithelial cells, and overexpression of any of these proteins affected the distribution of the others between nuclear speckles and nucleoplasm.
By radiation hybrid analysis, Nagase et al. (1997) mapped the SRM300 gene, or KIAA0324, to chromosome 16. By genomic sequence analysis, Blencowe et al. (2000) mapped the SRM300 gene to chromosome 16.
Hartz (2015) mapped the SRRM2 gene to chromosome 16p13.3 based on an alignment of the SRRM2 sequence (GenBank AB002322) with the genomic sequence (GRCh38).
By knockin, knockdown, and overexpression analyses in HEK293T cells, Xu et al. (2022) showed that SRRM2 mediated the nuclear condensation in the cell cycle, and that SRRM2-mediated nuclear condensation was essential for nuclear speckle formation. Mutation analysis revealed that the intrinsically disordered regions (IDRs) of SRRM2 were responsible for condensate formation in cells likely via phase separation, and that the condensates coacervated with RNA. Database search revealed that SRRM2 expression was upregulated in the bone marrow of acute myeloid leukemia (AML) patients, and knockdown analysis in the AML cell line THP-1 suggested that SRRM2 was associated with myeloid leukemia by promoting cell survival and repressing differentiation. Transcriptomic analysis of THP-1 cells SRRM2 knockdown showed that SRRM2 condensates maintain proper alternative splicing, as the differential alternative splicing events were dysregulated in myeloid cells with SRRM2 knockdown and the dysregulation was partly but not entirely associated with condensate formation. Further analysis with myeloid cells demonstrated that SRRM2 induced a FES (190030) splice isoform that attenuated innate inflammatory responses, and MUC1 (158340) isoforms that underwent shedding with oncogenic properties.
Using mass spectrometric analysis in 293T and HepG2 cells, Cui et al. (2023) identified SRRM2 as a nuclear proteins that interacts with ArgRS. Pull-down assays confirmed the interaction, and domain mapping revealed that the catalytic domain of ArgRS was necessary for the interaction. ArgRS catalytically inactivated by point mutations also retrieved SRRM2 from cell lysates. Deletion of the ArgRS leucine zipper, which integrates ArgRS into the multisynthetase complex (MSC) and thereby regulates its nuclear import, did not abolish the interaction with SRRM2; this and other findings indicated that ArgRS interacts with SRRM2 outside of the complete MSC. Immunofluorescence assay revealed the colocalization of ArgRS and SRRM2 in the nucleus, and the colocalization was ArgRS-specific and MSC-independent. ArgRS interaction with SRRM2 was modulated by external arginine concentrations, which in turn controlled nuclear ArgRS levels. ArgRS knockdown analysis showed that arginine-mediated changes in nuclear ArgRS levels affected SRRM2 mobility and changed the levels of SRRM2 available for RNA splicing in the nucleus, thereby impacting the processing of protein-coding mRNAs but not small noncoding RNAs (ncRNAs) and resulting in alternative splicing changes that led to different protein isoforms. Among the identified SRRM2-dependent splicing changes, a number of genes were shared between ArgRS and SRRM2, and the splicing of those genes was inversely regulated by both proteins. Moreover, the inverse regulation by ArgRS and SRRM2 likely contributed to changes in cellular metabolism and communication as part of a response to inflammation.
In 2 patients (patients 22 and 15) with MRD72, Cuinat et al. (2022) identified microdeletions of 66 kb and 270 kb on chromosome 16p, respectively, that included the SRRM2 gene.
Sheng et al. (2023) reported an 8-year-old girl with a 491.9-kb deletion on chromosome 16p, including the SRRM2 gene. She had speech and motor developmental delay, intellectual disability, attention deficits, and hyperactivity. She did not have facial dysmorphisms. Sheng et al. (2023) noted that the deletion included 17 genes, but that SRRM2 was the only gene predicted to cause disease by haploinsufficiency.
Pagnamenta et al. (2023) analyzed genomic rearrangements in 4 patients with an intellectual developmental disorder. All 4 patients, identified from data in the 100K Genomes Project database, had deletions of 248 to 482 kb including the SRRM2 gene. The distal deletion breakpoints were located in a 144-kb palindromic sequence located upstream of the SRRM2 gene.
Cuinat et al. (2022) reported heterozygous loss-of-function mutations (12 frameshift and 2 nonsense) in the SRRM2 gene (see, e.g., 606032.0001-606032.0007) in 20 unrelated patients with MRD72; 2 additional patients had microdeletions that included the SRRM gene. The mutations were identified by whole-exome sequencing, and 19 were confirmed to have occurred de novo. Segregation analysis showed that 1 patient inherited the mutation from a father who had developmental delay, and 1 patient was suspected to have inherited the mutation from an asymptomatic mother who was mosaic for the mutation. Segregation analysis was not performed in 1 patient. None of the mutations were present in the gnomAD database (v2.1.1).
In a patient (patient 1) with autosomal dominant intellectual developmental disorder-72 (MRD72; 620439), Cuinat et al. (2022) identified heterozygosity for a c.3346C-T transition (c.3346C-T, NM_016333.4) in the SRRM2 gene, resulting in a gln1116-to-ter (Q1116X) substitution. The mutation, which was identified by whole-exome sequencing and confirmed by Sanger sequencing, was shown to be de novo. The mutation was not present in the gnomAD database (v2.1.1).
In a patient (patient 2) with autosomal dominant intellectual developmental disorder-72 (MRD72; 620439), Cuinat et al. (2022) identified heterozygosity for 2-bp deletion (c.2970_2971del, NM_016333.4) in the SRRM2 gene, resulting in a frameshift and premature termination (Gly991ValfsTer31). The mutation, which was identified by whole-exome sequencing and confirmed by Sanger sequencing, was shown to be de novo. The mutation was not present in the gnomAD database (v2.1.1).
In a patient (patient 3) with autosomal dominant intellectual developmental disorder-72 (MRD72; 620439), Cuinat et al. (2022) identified heterozygosity for a c.4913C-G transversion (c.4913C-G, NM_016333.4) in the SRRM2 gene, resulting in a ser1638-to-ter (S1638X) substitution. The mutation, which was identified by whole-exome sequencing and confirmed by Sanger sequencing, was shown to be de novo. The mutation was not present in the gnomAD database (v2.1.1).
In a patient (patient 4) with autosomal dominant intellectual developmental disorder-72 (MRD72; 620430), Cuinat et al. (2022) identified heterozygosity for a 1-bp duplication (c.6709dupG, NM_016333.4) in the SRRM2 gene, resulting in a frameshift and premature termination (Ala2237GlyfsTer22). The mutation was identified by trio whole-exome sequencing and shown to be de novo. The mutation was not present in the gnomAD database (v2.1.1).
In a patient (patient 5) with autosomal dominant intellectual developmental disorder-72 (MRD72; 620439), Cuinat et al. (2022) identified heterozygosity for a c.6127C-T transition (c.6127C-T, NM_016333.4) in the SRRM2 gene, resulting in an arg2043-to-ter (R2043X) substitution. The mutation was identified by trio whole-exome sequencing and shown to be de novo. The mutation was not present in the gnomAD database (v2.1.1).
In a patient (patient 6) with autosomal dominant intellectual developmental disorder-72 (MRD72; 620439), Cuinat et al. (2022) identified heterozygosity for a c.4616C-A transversion (c.4616C-A, NM_016333.4) in the SRRM2 gene, resulting in a ser1539-to-ter (S1539X) substitution. The mutation was identified by trio whole-exome sequencing and shown to be de novo. The mutation was not present in the gnomAD database (v2.1.1).
In a patient (patient 7) with autosomal dominant intellectual developmental disorder-72 (MRD72; 620439), Cuinat et al. (2022) identified heterozygosity for a 4-bp deletion (c.2782_2785del, NM_016333.4) in the SRRM2 gene, resulting in a frameshift and premature termination (Arg928AlafsTer13). The mutation was identified by trio whole-exome sequencing and shown to be de novo. The mutation was not present in the gnomAD database (v2.1.1).
Blencowe, B. J., Bauren, G., Eldridge, A. G., Issner, R., Nickerson, J. A., Rosonina, E., Sharp, P. A. The SRm160/300 splicing coactivator subunits. RNA 6: 111-120, 2000. [PubMed: 10668804] [Full Text: https://doi.org/10.1017/s1355838200991982]
Cui, H., Diedrich, J. K., Wu, D. C., Lim, J. J., Nottingham, R. M., Moresco, J. J., Yates, J. R., III, Blencowe, B. J., Lambowitz, A. M., Schimmel, P. Arg-tRNA synthetase links inflammatory metabolism to RNA splicing and nuclear trafficking via SRRM2. Nature Cell Biol. 25: 592-603, 2023. Note: Erratum: Nature Cell Biol. 25: 1073 only, 2023. [PubMed: 37059883] [Full Text: https://doi.org/10.1038/s41556-023-01118-8]
Cuinat, S., Nizon, M., Isidor, B., Stegmann, A., van Jaarsveld, R. H., van Gassen, K. L., van der Smagt, J. J., Volker-Touw, C. M. L., Holwerda, S. J. B., Terhal, P. A., Schuhmann, S., Vasileiou, G., and 39 others. Loss-of-function variants in SRRM2 cause a neurodevelopmental disorder. Genet. Med. 24: 1774-1780, 2022. [PubMed: 35567594] [Full Text: https://doi.org/10.1016/j.gim.2022.04.011]
Hartz, P. A. Personal Communication. Baltimore, Md. 11/19/2015.
Nagase, T., Ishikawa, K., Nakajima, D., Ohira, M., Seki, N., Miyajima, N., Tanaka, A., Kotani, H., Nomura, N., Ohara, O. Prediction of the coding sequences of unidentified human genes. VII. The complete sequences of 100 new cDNA clones from brain which can code for large proteins in vitro. DNA Res. 4: 141-150, 1997. [PubMed: 9205841] [Full Text: https://doi.org/10.1093/dnares/4.2.141]
Pagnamenta, A. T., Yu, J., Willis, T. A., Hashim, M., Seaby, E. G., Walker, S., Xian, J., Cheng, E. W. Y., Taylor Tavares, A. L., Forzano, F., Cox, H., Dabir, T., Brady, A. F., Ghali, N., Atanur, S. S., Ennis, S., Baralle, D., Taylor, J. C. A palindrome-like structure on 16p13.3 is associated with the formation of complex structural variations and SRRM2 haploinsufficiency. Hum. Mutat. 2023: 6633248, 2023.
Sawada, Y., Miura, Y., Umeki, K., Tamaoki, T., Fujinaga, K., Ohtaki, S. Cloning and characterization of a novel RNA-binding protein SRL300 with RS domains. Biochim. Biophys. Acta 1492: 191-195, 2000. [PubMed: 11004489] [Full Text: https://doi.org/10.1016/s0167-4781(00)00065-8]
Sheng, W., Yu, X., Shu, J., Cai, C. Correspondence on 'Loss-of-function variants in SRRM2 cause a neurodevelopmental disorder' by Cuinat et al. Genet. Med. 25: 100878, 2023. [PubMed: 37272925] [Full Text: https://doi.org/10.1016/j.gim.2023.100878]
Xu, S., Lai, S.-K., Sim, D. Y., Ang, W. S. L., Li, H. Y., Roca, X. SRRM2 organizes splicing condensates to regulate alternative splicing. Nucleic Acids Res. 50: 8599-8614, 2022. [PubMed: 35929045] [Full Text: https://doi.org/10.1093/nar/gkac669]
Zimowska, G., Shi, J., Munguba, G., Jackson, M. R., Alpatov, R., Simmons, M. N., Shi, Y., Sugrue, S. P. Pinin/DRS/memA interacts with SRp75, SRm300 and SRrp130 in corneal epithelial cells. Invest. Ophthal. Vis. Sci. 44: 4715-4723, 2003. [PubMed: 14578391] [Full Text: https://doi.org/10.1167/iovs.03-0240]