The TREX (TRanscription-EXport) complex is a conserved eukaryotic multi-protein complex that couples mRNA transcription and nuclear export.[1] The TREX complex travels across transcribed genes with RNA polymerase II.[2] TREX binds mRNA and recruits transport proteins NXF1 and NXT1 (yeast Mex67 and Mtr2), which shuttle the mRNA out of the nucleus.[3][4][5][6] The TREX complex plays an important role in genome stability and neurodegenerative diseases.[7]

Role in mRNA nuclear export

Nuclear export of mRNAs facilitated by TREX complex.[1]

During transcription elongation, the THO complex follows RNA polymerase II and interacts with transcription factors along the entire transcribed region.[1] Then, the carboxy-terminal domain (CTD) of RNA polymerase II recruits the 3'-end processing factors/transcription termination factors, which load DEAD-box RNA helicase UAP56 and RNA export adapter ALYREF. This forms the complete TREX complex. At the end of transcription, after the 3'-end of mRNA is formed and the mRNA is released from transcription site, the mRNA is transferred from UAP56 to ALYREF. UAP56 then dissociates, allowing the heterodimeric export receptor NXF1-NXT1 to bind as it recognizes the mRNA indirectly through ALYREF. Further arrangements of mRNA result in ALYREF's release. Finally, the NXF1-NXT1 dimer facilitates mRNA nuclear transport to the cytoplasm through direct interaction with the nuclear pore complex.

Composition and conservation in eukaryotic species

THO complex

Crystal structure of the THO complex (blue) bound to Sub2 (grey). PDB: 5suq[8]

The human THO complex comprises six subunits, THOC1, −2, –3, −5, –6, and −7. Four of them have counterparts in Saccharomyces cerevisiae: THOC1 (yeast Hpr1), −2 (yeast Tho2), −3 (yeast Tex3), and −7 (yeast Mft1).[7][9] THOC1 is the first protein identified in THO complex. THOC2 is the largest subunit of TREX. It acts as a scaffold for the formation of the complex. The C-terminal domain of THOC2 directly interacts with nucleic acids. Mutational variants of THOC2 have been associated with syndromic intellectual disabilities, causing seizures, tremors, speech delays, and more.[10][11] THOC 3 and 6 both contains WD40 repeat motifs that allow interaction with other THO proteins.[12] THOC5 and THOC7 binds tightly and forms a dimer at their coiled coil domain (CCD). Four THO complexes form a tetramer, and each THO complex binds with one UAP56 protein at THOC2 and THOC1.

DDX39/UAP56

DDX39, or U2AF65-associated protein 56 (UAP56, Sub2 in yeast) is a DEAD-box ATPase essential for pre-mRNA splicing,[13] but is also a key component of the TREX complex. DDX39 is very similar to UAP56, sharing 90% of the amino acid sequence.[1] UAP56 travels along genes with the THO complex, where it interacts with the sugar-phosphate backbone of the mRNA.[14] UAP56 functions to recruit ALYREF, an RNA export adaptor, to the spliced or intronless mRNA.[15][6] After transfer of the mRNA from UAP56 to ALYREF, UAP56 dissociates from the complex, allowing the binding of export factor NXF1 to ALYREF at the same site.[16][4]

Crystal Structure of Sub2 (grey) and Yra1 (purple) complexed with mRNA (orange). PDB: 5sup[8]
DDX39B
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesDDX39B, BAT1, D6S81E, UAP56, DEAD-box helicase 39B, DExD-box helicase 39B
External IDsOMIM: 142560 MGI: 99240 HomoloGene: 48376 GeneCards: DDX39B
Orthologs
SpeciesHumanMouse
Entrez

7919

53817

Ensembl

ENSMUSG00000019432

UniProt

Q13838

Q9Z1N5

RefSeq (mRNA)

NM_004640
NM_080598

NM_001252457
NM_019693

RefSeq (protein)

NP_004631
NP_542165

NP_001239386
NP_062667

Location (UCSC)Chr 6: 31.53 – 31.54 MbChr 17: 35.46 – 35.47 Mb
PubMed search[19][20]
Wikidata
View/Edit HumanView/Edit Mouse

DDX39a

In mammalian cells, a paralog of DDX39b, DDX39a, exists, and is somewhat functionally redundant. Knockdown of both paralogs is required to block mRNA export,[21][22] but depletion of either paralog affects different forms of mRNAs.[23] DDX39b is shown to associate with THO and ALYREF, and DDX39a with CIP29 and ALYREF.[24]

ALYREF

ALYREF (Yra1 in yeast) is an essential RNA export adapter involved in the export of both spliced and intronless mRNAs.[25] The N and C-termini of ALYREF both contain UAP56-bonding motifs (UBMs), which are necessary for its interaction with UAP56.[21] ALYREF also contains an RNA recognition motif (RRM) that weakly binds RNA,[26] and is flanked by two arginine-rich RNA binding sites. ALYREF alone cannot bind mRNA effectively, and requires interaction with UAP56 to bind the mRNA in the TREX Complex (see Figure 3). These arginine-rich sites are also necessary for ALYREF's interaction with export receptor NXF1, which stimulates the transfer of the mRNA from ALYREF to NXF1.[5] Like UAP56, ALYREF dissociates prior to nuclear export of the mRNA.[16][27] The unstructured and flexible nature of ALYREF indicates it may play a key role in packaging the mRNA and proteins into a messenger ribonuclear protein (mRNP) for nuclear export.[28]

UIF/FYTTD1

UIF, identified through gene homology of ALYREF's UAP56-binding domain, is functionally redundant with ALYREF. Knockdown of ALYREF in mammalian cells results in large upregulation of UIF. UIF can associate with the other TREX complex components in an RNA-independent manner.[21] UIF is speculated to associate with alternative TREX complexes in place of ALYREF, perhaps acting on certain types or mRNAs.

CHTOP

Originally identified as a RNA-binding protein involved in cell cycle regulation,[29] CHTOP contains two UBMs like those in ALYREF and UIF, and is thought to function in a similar manner to ALYREF. CHTOP has also been shown to stimulate UAP56 ATPase activity.[30] CHTOP is speculated to associate with alternative TREX complexes in place of UAP56, perhaps acting on specific types or mRNAs.

SARNP/CIP29

SARNP/CIP29 (yeast Tho1), identified alongside yeast Tho2,[31] forms a trimeric complex with UAP56 and ALYREF,[32] and has been shown to preferentially associate with DDX39a.[24] SARNP stimulates UAP56 ATPase activity.[30][33]

Conservation of the TREX Complex
Yeast Drosophila Mammals
THO components Hpr1 Thoc1 Thoc1 (hHpr1)
Tho2 Thoc2 Thoc2
Thp2
Mft1 Thoc7 Thoc7
Thoc5 Thoc5 (FMIP)
Thoc6 Thoc6
Tex1 Thoc3 Thoc3 (hTEX1)
DEAD-box type helicase Sub2 Uap56 Uap56
DDX39
Adaptor mRNA binding protein Yra1 Aly ALYREF

Associated proteins

NXF1

NXF1(Mex67p in yeast), also known as nuclear RNA export factor 1, is a multi-domain protein composed of one conserved N-terminal RNA recognition and four leucine-rich repeat motifs, a central NTF2-like domain, and a C-terminal ubiquitin associated domain that mediates interactions with nucleoporins. The NTF2-like domain is able to form heterodimers with NTF2-related export protein-1 (NXT1). The heterodimer binds mRNAs processed by the TREX complex and assists the TREX complex in the nuclear export process.[34][35]

NXT1

NXT1 (Mtr2p in yeast) is also known as p15. It shuttles between the nucleus and the cytoplasm acting as an active nuclear transport protein. NXT1 binds specifically to Ran-GTP and localizes to the nuclear pore complex in mammalian cells. It also stabilizes and forms heterodimers with NXF1. The heterodimer binds mRNAs processed by the TREX complex and assists the TREX complex in the nuclear export process.[36]

NCBP1 & NCBP3

NCBP1 and NCBP3 are both part of the cap-binding complex. The two proteins interact with each other as well as the TREX complex in facilitating the mRNA export from the nucleus to the cytoplasm. NCBP3 further interact with exon junction complex proteins for mRNA splicing and stability.[37]

Role in genome stability, mutations, and diseases

The TREX complex is a conserved protein complex that couples transcription to mRNA export and is linked to genome stability and several disorders.

Genome stability

The TREX complex plays an important role in genome stability. Newly formed RNA strands can hybridize with the single-stranded template DNA sequence during transcription, leading to an R-loop.[7] The R-loop makes the opposing DNA strand more susceptible to cleavage, which can cause DNA damage in cells.[7] The TREX complex associates with the RNA polymerase and newly formed RNA, sequestering the RNA and, therefore, preventing its hybridization to the DNA strand, improving genome stability.[7]

Neurodegenerative diseases

The TREX complex is associated with several neurodegenerative and neurodevelopmental disorders. These disorders are caused by mutations in the TREX complex itself or in other genes.[7]

Direct mutations in TREX subunits

Several mutations in the THOC2 gene, part of the THO complex, are associated with disease. For example, missense mutations, or a change in a nucleotide that results in the encoding of a different amino acid, in this gene and translocations on the X chromosome are associated with intellectual disabilities.[7][38]

The THOC6 gene, part of the THO complex, plays a role in the development of the brain and other organs. Mutations on this gene leads to the incorrect localization of the protein in the cytoplasm, an essential process for neural and organ development.[7] A homozygous mutation in this gene can lead to not only intellectual disability, but cardiac defects and brain malformation.[7]

Mutations in other genes

Mutations in other genes can also have an indirect dependence on the TREX complex and lead to disease, including familial amyotrophic lateral sclerosis(ALS). ALS is a rare neurodegenerative disease that leads to the death of motor neurons in the brain, resulting in the loss of voluntary movement.[39] In the familial form of the disease, a GGGGCC repeat in an intron of the C9ORF72 gene is expanded in the pre-mRNA, which is exported to the cytoplasm and forms RNA foci.[7] ALYREF binds to the repeat expansion, and an excess recruitment promotes its export.[7] A mutation that disrupts its activity suppresses neurodegeneration, and is enhanced by CHTOP and NXF1.[7]

See also

References

  1. 1 2 3 4 Katahira, Jun (2012). "mRNA export and the TREX complex". Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms. 1819 (6): 507–513. doi:10.1016/j.bbagrm.2011.12.001. ISSN 0006-3002. PMID 22178508.
  2. ↑ Strässer, Katja; Masuda, Seiji; Mason, Paul; Pfannstiel, Jens; Oppizzi, Marisa; Rodriguez-Navarro, Susana; Rondón, Ana G.; Aguilera, Andres; Struhl, Kevin; Reed, Robin; Hurt, Ed (2002-05-16). "TREX is a conserved complex coupling transcription with messenger RNA export". Nature. 417 (6886): 304–308. Bibcode:2002Natur.417..304S. doi:10.1038/nature746. ISSN 0028-0836. PMID 11979277. S2CID 1112194.
  3. ↑ Strässer, K.; Hurt, E. (2001-10-11). "Splicing factor Sub2p is required for nuclear mRNA export through its interaction with Yra1p". Nature. 413 (6856): 648–652. Bibcode:2001Natur.413..648S. doi:10.1038/35098113. ISSN 0028-0836. PMID 11675790. S2CID 4361359.
  4. 1 2 Köhler, Alwin; Hurt, Ed (2007). "Exporting RNA from the nucleus to the cytoplasm". Nature Reviews. Molecular Cell Biology. 8 (10): 761–773. doi:10.1038/nrm2255. ISSN 1471-0080. PMID 17786152. S2CID 10836137.
  5. 1 2 Hautbergue, Guillaume M.; Hung, Ming-Lung; Golovanov, Alexander P.; Lian, Lu-Yun; Wilson, Stuart A. (2008). "Mutually exclusive interactions drive handover of mRNA from export adaptors to TAP". Proceedings of the National Academy of Sciences. 105 (13): 5154–5159. Bibcode:2008PNAS..105.5154H. doi:10.1073/pnas.0709167105. ISSN 0027-8424. PMC 2278192. PMID 18364396.
  6. 1 2 Taniguchi, Ichiro; Ohno, Mutsuhito (2008). "ATP-dependent recruitment of export factor Aly/REF onto intronless mRNAs by RNA helicase UAP56". Molecular and Cellular Biology. 28 (2): 601–608. doi:10.1128/MCB.01341-07. ISSN 1098-5549. PMC 2223434. PMID 17984224.
  7. 1 2 3 4 5 6 7 8 9 10 11 12 Heath, Catherine G.; Viphakone, Nicolas; Wilson, Stuart A. (2016-10-01). "The role of TREX in gene expression and disease". Biochemical Journal. 473 (19): 2911–2935. doi:10.1042/BCJ20160010. ISSN 0264-6021. PMC 5095910. PMID 27679854.
  8. 1 2 Ren, Yi; Schmiege, Philip; Blobel, Günter (2017-01-06). Weis, Karsten (ed.). "Structural and biochemical analyses of the DEAD-box ATPase Sub2 in association with THO or Yra1". eLife. 6: e20070. doi:10.7554/eLife.20070. ISSN 2050-084X. PMC 5218534. PMID 28059701.
  9. ↑ Mitchell, Alex L; Attwood, Teresa K; Babbitt, Patricia C; Blum, Matthias; Bork, Peer; Bridge, Alan; Brown, Shoshana D; Chang, Hsin-Yu; El-Gebali, Sara; Fraser, Matthew I; Gough, Julian; Haft, David R; Huang, Hongzhan; Letunic, Ivica; Lopez, Rodrigo (2018-11-06). "InterPro in 2019: improving coverage, classification and access to protein sequence annotations". Nucleic Acids Research. 47 (D1): D351–D360. doi:10.1093/nar/gky1100. ISSN 0305-1048. PMC 6323941. PMID 30398656.
  10. ↑ Peña, Álvaro; Gewartowski, Kamil; Mroczek, Seweryn; Cuéllar, Jorge; Szykowska, Aleksandra; Prokop, Andrzej; Czarnocki-Cieciura, Mariusz; Piwowarski, Jan; Tous, Cristina; Aguilera, Andrés; Carrascosa, José L; Valpuesta, José María; Dziembowski, Andrzej (2012-03-21). "Architecture and nucleic acids recognition mechanism of the THO complex, an mRNP assembly factor: Structure and function of the THO complex". The EMBO Journal. 31 (6): 1605–1616. doi:10.1038/emboj.2012.10. PMC 3321177. PMID 22314234.
  11. ↑ Kumar, Raman; Corbett, Mark A.; van Bon, Bregje W. M.; Woenig, Joshua A.; Weir, Lloyd; Douglas, Evelyn; Friend, Kathryn L.; Gardner, Alison; Shaw, Marie; Jolly, Lachlan A.; Tan, Chuan; Hunter, Matthew F.; Hackett, Anna; Field, Michael; Palmer, Elizabeth E. (2015-08-06). "THOC2 Mutations Implicate mRNA-Export Pathway in X-Linked Intellectual Disability". American Journal of Human Genetics. 97 (2): 302–310. doi:10.1016/j.ajhg.2015.05.021. ISSN 1537-6605. PMC 4573269. PMID 26166480.
  12. ↑ Masuda, Seiji; Das, Rita; Cheng, Hong; Hurt, Ed; Dorman, Nijsje; Reed, Robin (2005-07-01). "Recruitment of the human TREX complex to mRNA during splicing". Genes & Development. 19 (13): 1512–1517. doi:10.1101/gad.1302205. ISSN 0890-9369. PMC 1172058. PMID 15998806.
  13. ↑ Fleckner, J.; Zhang, M.; Valcárcel, J.; Green, M. R. (1997-07-15). "U2AF65 recruits a novel human DEAD box protein required for the U2 snRNP-branchpoint interaction". Genes & Development. 11 (14): 1864–1872. doi:10.1101/gad.11.14.1864. ISSN 0890-9369. PMID 9242493. S2CID 28531804.
  14. ↑ Linder, Patrick; Jankowsky, Eckhard (2011). "From unwinding to clamping — the DEAD box RNA helicase family". Nature Reviews Molecular Cell Biology. 12 (8): 505–516. doi:10.1038/nrm3154. ISSN 1471-0072. PMID 21779027. S2CID 2037710.
  15. ↑ Luo, M. L.; Zhou, Z.; Magni, K.; Christoforides, C.; Rappsilber, J.; Mann, M.; Reed, R. (2001). "Pre-mRNA splicing and mRNA export linked by direct interactions between UAP56 and Aly". Nature. 413 (6856): 644–647. Bibcode:2001Natur.413..644L. doi:10.1038/35098106. PMID 11675789. S2CID 4395388.
  16. 1 2 Kiesler, Eva; Miralles, Francesc; Visa, Neus (2002-05-14). "HEL/UAP56 Binds Cotranscriptionally to the Balbiani Ring Pre-mRNA in an Intron-Independent Manner and Accompanies the BR mRNP to the Nuclear Pore". Current Biology. 12 (10): 859–862. doi:10.1016/S0960-9822(02)00840-0. ISSN 0960-9822. PMID 12015125. S2CID 17926674.
  17. 1 2 3 ENSG00000225073, ENSG00000237889, ENSG00000229496, ENSG00000215425, ENSG00000235439, ENSG00000225859, ENSG00000230624 GRCh38: Ensembl release 89: ENSG00000198563, ENSG00000225073, ENSG00000237889, ENSG00000229496, ENSG00000215425, ENSG00000235439, ENSG00000225859, ENSG00000230624 - Ensembl, May 2017
  18. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000019432 - Ensembl, May 2017
  19. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  20. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  21. 1 2 3 Hautbergue, Guillaume M.; Hung, Ming-Lung; Walsh, Matthew J.; Snijders, Ambrosius P.L.; Chang, Chung-Te; Jones, Rachel; Ponting, Chris P.; Dickman, Mark J.; Wilson, Stuart A. (2009). "UIF, a New mRNA Export Adaptor that Works Together with REF/ALY, Requires FACT for Recruitment to mRNA". Current Biology. 19 (22): 1918–1924. doi:10.1016/j.cub.2009.09.041. PMC 2828547. PMID 19836239.
  22. ↑ Pryor, A. (2004-03-26). "Growth-regulated expression and G0-specific turnover of the mRNA that encodes URH49, a mammalian DExH/D box protein that is highly related to the mRNA export protein UAP56". Nucleic Acids Research. 32 (6): 1857–1865. doi:10.1093/nar/gkh347. ISSN 1362-4962. PMC 390356. PMID 15047853.
  23. ↑ Yamazaki, Tomohiro; Fujiwara, Naoko; Yukinaga, Hiroko; Ebisuya, Miki; Shiki, Takuya; Kurihara, Tomoya; Kioka, Noriyuki; Kambe, Taiho; Nagao, Masaya; Nishida, Eisuke; Masuda, Seiji (2010-08-15). Weis, Karsten (ed.). "The Closely Related RNA helicases, UAP56 and URH49, Preferentially Form Distinct mRNA Export Machineries and Coordinately Regulate Mitotic Progression". Molecular Biology of the Cell. 21 (16): 2953–2965. doi:10.1091/mbc.e09-10-0913. ISSN 1059-1524. PMC 2921121. PMID 20573985.
  24. 1 2 Yamazaki, Tomohiro; Fujiwara, Naoko; Yukinaga, Hiroko; Ebisuya, Miki; Shiki, Takuya; Kurihara, Tomoya; Kioka, Noriyuki; Kambe, Taiho; Nagao, Masaya; Nishida, Eisuke; Masuda, Seiji (2010). "The Closely Related RNA helicases, UAP56 and URH49, Preferentially Form Distinct mRNA Export Machineries and Coordinately Regulate Mitotic Progression". Molecular Biology of the Cell. 21 (16): 2953–2965. doi:10.1091/mbc.e09-10-0913. PMC 2921121. PMID 20573985.
  25. ↑ Rodrigues, João P.; Rode, Michaela; Gatfield, David; Blencowe, Benjamin J.; Carmo-Fonseca, Maria; Izaurralde, Elisa (2001-01-30). "REF proteins mediate the export of spliced and unspliced mRNAs from the nucleus". Proceedings of the National Academy of Sciences. 98 (3): 1030–1035. Bibcode:2001PNAS...98.1030R. doi:10.1073/pnas.98.3.1030. ISSN 0027-8424. PMC 14703. PMID 11158589.
  26. ↑ Golovanov, Alexander P.; Hautbergue, Guillaume M.; Tintaru, Aura M.; Lian, Lu-Yun; Wilson, Stuart A. (2006-11-01). "The solution structure of REF2-I reveals interdomain interactions and regions involved in binding mRNA export factors and RNA". RNA. 12 (11): 1933–1948. doi:10.1261/rna.212106. ISSN 1355-8382. PMC 1624900. PMID 17000901.
  27. ↑ Kim, V.N. (2001-04-17). "The Y14 protein communicates to the cytoplasm the position of exon-exon junctions". The EMBO Journal. 20 (8): 2062–2068. doi:10.1093/emboj/20.8.2062. PMC 125236. PMID 11296238.
  28. ↑ Björk, Petra; Wieslander, Lars (2015-06-02). "The Balbiani Ring Story: Synthesis, Assembly, Processing, and Transport of Specific Messenger RNA–Protein Complexes". Annual Review of Biochemistry. 84 (1): 65–92. doi:10.1146/annurev-biochem-060614-034150. ISSN 0066-4154. PMID 26034888.
  29. ↑ Zullo, Alfred J.; Michaud, Monia; Zhang, Weiping; Grusby, Michael J. (2009). "Identification of the Small Protein Rich in Arginine and Glycine (SRAG)". Journal of Biological Chemistry. 284 (18): 12504–12511. doi:10.1074/jbc.M809436200. PMC 2673316. PMID 19254951.
  30. 1 2 Chang, Chung-Te; Hautbergue, Guillaume M; Walsh, Matthew J; Viphakone, Nicolas; van Dijk, Thamar B; Philipsen, Sjaak; Wilson, Stuart A (2013-01-08). "Chtop is a component of the dynamic TREX mRNA export complex". The EMBO Journal. 32 (3): 473–486. doi:10.1038/emboj.2012.342. ISSN 0261-4189. PMC 3567497. PMID 23299939.
  31. ↑ Piruat, J. I. (1998-08-17). "A novel yeast gene, THO2, is involved in RNA pol II transcription and provides new evidence for transcriptional elongation-associated recombination". The EMBO Journal. 17 (16): 4859–4872. doi:10.1093/emboj/17.16.4859. PMC 1170815. PMID 9707445.
  32. ↑ Dufu, Kobina; Livingstone, Michaela J.; Seebacher, Jan; Gygi, Steven P.; Wilson, Stuart A.; Reed, Robin (2010-09-15). "ATP is required for interactions between UAP56 and two conserved mRNA export proteins, Aly and CIP29, to assemble the TREX complex". Genes & Development. 24 (18): 2043–2053. doi:10.1101/gad.1898610. ISSN 0890-9369. PMC 2939366. PMID 20844015.
  33. ↑ Sugiura, Takeyuki; Sakurai, Kayo; Nagano, Yuki (2007). "Intracellular characterization of DDX39, a novel growth-associated RNA helicase". Experimental Cell Research. 313 (4): 782–790. doi:10.1016/j.yexcr.2006.11.014. PMID 17196963.
  34. ↑ Segref, A. (1997-06-01). "Mex67p, a novel factor for nuclear mRNA export, binds to both poly(A)+ RNA and nuclear pores". The EMBO Journal. 16 (11): 3256–3271. doi:10.1093/emboj/16.11.3256. ISSN 1460-2075. PMC 1169942. PMID 9214641.
  35. ↑ Teplova, Marianna; Wohlbold, Lara; Khin, Nyan W; Izaurralde, Elisa; Patel, Dinshaw J (2011). "Structure-function studies of nucleocytoplasmic transport of retroviral genomic RNA by mRNA export factor TAP". Nature Structural & Molecular Biology. 18 (9): 990–998. doi:10.1038/nsmb.2094. ISSN 1545-9993. PMC 3167930. PMID 21822283.
  36. ↑ Black, Ben E.; Lévesque, Lyne; Holaska, James M.; Wood, Todd C.; Paschal, Bryce M. (1999). "Identification of an NTF2-Related Factor That Binds Ran-GTP and Regulates Nuclear Protein Export". Molecular and Cellular Biology. 19 (12): 8616–8624. doi:10.1128/mcb.19.12.8616. ISSN 0270-7306. PMC 84993. PMID 10567585.
  37. ↑ Gebhardt, Anna; Habjan, Matthias; Benda, Christian; Meiler, Arno; Haas, Darya A.; Hein, Marco Y.; Mann, Angelika; Mann, Matthias; Habermann, Bianca; Pichlmair, Andreas (2015). "mRNA export through an additional cap-binding complex consisting of NCBP1 and NCBP3". Nature Communications. 6 (1): 8192. Bibcode:2015NatCo...6.8192G. doi:10.1038/ncomms9192. ISSN 2041-1723. PMC 4595607. PMID 26382858.
  38. ↑ "Missense Mutation". Genome.gov. Retrieved 2022-10-24.
  39. ↑ "What is ALS?". The ALS Association. Retrieved 2022-10-25.
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