Eukaryotic cells arose ~1.5 billion years ago, with the endomembrane system a central feature, facilitating evolution of intracellular compartments. Endomembranes include the nuclear envelope (NE) dividing the cytoplasm and nucleoplasm. The NE possesses universal features: a double lipid bilayer membrane, nuclear pore complexes (NPCs), and continuity with the endoplasmic reticulum, indicating common evolutionary origin. However, levels of specialization between lineages remains unclear, despite distinct mechanisms underpinning various nuclear activities. Several distinct modes of molecular evolution facilitate organellar diversification and to understand which apply to the NE, we exploited proteomic datasets of purified nuclear envelopes from model systems for comparative analysis. We find enrichment of core nuclear functions amongst the widely conserved proteins to be less numerous than lineage-specific cohorts, but enriched in core nuclear functions. This, together with consideration of additional evidence, suggests that, despite a common origin, the NE has evolved as a highly diverse organelle with significant lineage-specific functionality.

Division of Biological Chemistry and Drug Discovery School of Life Sciences University of Dundee Dundee UK

Institute of Parasitology Biology Centre Czech Academy of Sciences České Czech Republic

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Betts HC, Puttick MN, Clark JW, et al. Integrated genomic and fossil evidence illuminates life’s early evolution and eukaryote origin. Nat Ecol Evol. 2018;2(10):1556–1562. PubMed PMC

Dacks JB, Field MC, Buick R, et al. The changing view of eukaryogenesis - fossils, cells, lineages and how they all come together. J Cell Sci. 2016;129(20):3695–3703. PubMed

Szathmary E, Smith JM.. The major evolutionary transitions. Nature. 1995;374(6519):227–232. PubMed

Williams TA, Foster PG, Nye TM, et al. A congruent phylogenomic signal places eukaryotes within the Archaea. Proc Biol Sci. 2012;279(1749):4870–4879. PubMed PMC

Winker S, Woese CR. A definition of the domains Archaea, bacteria and eucarya in terms of small subunit ribosomal RNA characteristics. Syst Appl Microbiol. 1991;14(4):305–310. PubMed

Tang Q, Pang K, Yuan X, et al. A one-billion-year-old multicellular chlorophyte. Nat Ecol Evol. 2020;4(4):543–549. PubMed PMC

Sagan L. On the origin of mitosing cells. J Theor Biol. 1967;14(3):255–274. PubMed

Elias M, Brighouse A, Gabernet-Castello C, et al. Sculpting the endomembrane system in deep time: high resolution phylogenetics of Rab GTPases. J Cell Sci. 2012;125(10):2500–2508. PubMed PMC

Vicente JJ, Wordeman L. Mitosis, microtubule dynamics and the evolution of kinesins. Exp Cell Res. 2015;334(1):61–69. PubMed PMC

More K, Klinger CM, Barlow LD, et al. Evolution and natural history of membrane trafficking in eukaryotes. Curr Biol. 2020;30(10):R553–R64. PubMed

Dacks JB, Field MC. Evolutionary origins and specialisation of membrane transport. Curr Opin Cell Biol. 2018;53:70–76. PubMed PMC

Pereira-Leal JB. The Ypt/Rab family and the evolution of trafficking in fungi. Traffic. 2008;9(1):27–38. PubMed

Sparvoli D, Zoltner M, Cheng CY, et al. Diversification of CORVET tethers facilitates transport complexity in tetrahymena thermophila. J Cell Sci. 2020;133(3):3. PubMed PMC

Rout MP, Field MC. The evolution of organellar coat complexes and organization of the eukaryotic cell. Annu Rev Biochem. 2017;86(1):637–657. PubMed

Martin WF, Garg S, Zimorski V. Endosymbiotic theories for eukaryote origin. Philos Trans R Soc Lond B Biol Sci. 2015;370(1678):20140330. PubMed PMC

Pittis AA, Gabaldon T. Late acquisition of mitochondria by a host with chimaeric prokaryotic ancestry. Nature. 2016;531(7592):101–104. PubMed PMC

Field MC, Rout MP. Pore timing: the evolutionary origins of the nucleus and nuclear pore complex. F1000Res. 2019;8:369. PubMed PMC

Xie Y, Ren Y. Mechanisms of nuclear mRNA export: a structural perspective. Traffic. 2019;20(11):829–840. PubMed PMC

Thaller DJ, Allegretti M, Borah S, et al. LEM protein surveillance system is poised to directly monitor the nuclear envelope and nuclear transport system. Elife. 2019;8. DOI:10.7554/eLife.45284.. PubMed DOI PMC

Vietri M, Radulovic M, Stenmark H. The many functions of ESCRTs. Nat Rev Mol Cell Biol. 2020;21(1):25–42. PubMed

Aoki K, Hayashi H, Furuya K, et al. Breakage of the nuclear envelope by an extending mitotic nucleus occurs during anaphase in Schizosaccharomyces japonicus. Genes Cells. 2011;16(9):911–926. PubMed

Sazer S, Lynch M, Needleman D. Deciphering the evolutionary history of open and closed mitosis. Curr Biol. 2014;24(22):R1099–103. PubMed PMC

Devos DP, Graf R, Field MC. Evolution of the nucleus. Curr Opin Cell Biol. 2014;28:8–15. PubMed PMC

Meier I, Richards EJ, Evans DE. Cell biology of the plant nucleus. Annu Rev Plant Biol. 2017;68(1):139–172. PubMed

Koreny L, Field MC. Ancient eukaryotic origin and evolutionary plasticity of nuclear lamina. Genome Biol Evol. 2016;8(9):2663–2671. PubMed PMC

Ciska M, Masuda K. Moreno Diazde la Espina S. Lamin-like analogues in plants: the characterization of NMCP1 in allium cepa. J Exp Bot. 2013;64(6):1553–1564. PubMed PMC

DuBois KN, Alsford S, Holden JM, et al. NUP-1 is a large coiled-coil nucleoskeletal protein in trypanosomes with lamin-like functions. PLoS Biol. 2012;10(3):e1001287. PubMed PMC

Maishman L, Obado SO, Alsford S, et al. Co-dependence between trypanosome nuclear lamina components in nuclear stability and control of gene expression. Nucleic Acids Res. 2016;44(22):10554–10570. PubMed PMC

Padilla-Mejia NE, Koreny L, Holden J, et al. A hub and spoke model of assembly for the trypanosome nuclear lamina. J Cell Sci. 2020. PubMed PMC

Strambio-de-Castillia C, Blobel G, Rout MP. Isolation and characterization of nuclear envelopes from the yeast Saccharomyces. J Cell Biol. 1995;131(1):19–31. PubMed PMC

Hirano Y, Asakawa H, Sakuno T, et al. Nuclear envelope proteins modulating the heterochromatin formation and functions in fission yeast. Cells. 2020;9(8):8. PubMed PMC

Gonzalez Y, Saito A, Sazer S. Fission yeast Lem2 and Man1 perform fundamental functions of the animal cell nuclear lamina. Nucleus. 2012;3(1):60–76. PubMed PMC

Aitchison JD, Rout MP. The yeast nuclear pore complex and transport through it. Genetics. 2012;190(3):855–883. PubMed PMC

Akiyoshi B, Gull K. Discovery of unconventional kinetochores in kinetoplastids. Cell. 2014;156(6):1247–1258. PubMed PMC

Field MC. The kinetochore and the origin of eukaryotic chromosome segregation. Proc Natl Acad Sci U S A. 2019;116(26):12596–12598. PubMed PMC

Ebenezer TE, Zoltner M, Burrell A, et al. Transcriptome, proteome and draft genome of Euglena gracilis. BMC Biol. 2019;17(1):11. PubMed PMC

Kenny NJ, Francis WR, Rivera-Vicens RE, et al. Tracing animal genomic evolution with the chromosomal-level assembly of the freshwater sponge Ephydatia muelleri. Nat Commun. 2020;11(1):3676. PubMed PMC

Leger MM, Kolisko M, Kamikawa R, et al. Organelles that illuminate the origins of trichomonas hydrogenosomes and giardia mitosomes. Nat Ecol Evol. 2017;1(4):0092. PubMed PMC

Lax G, Eglit Y, Eme L, et al. Hemimastigophora is a novel supra-kingdom-level lineage of eukaryotes. Nature. 2018;564(7736):410–414. PubMed

Tang S, Lomsadze A, Borodovsky M. Identification of protein coding regions in RNA transcripts. Nucleic Acids Res. 2015;43(12):e78. PubMed PMC

Schirmer EC, Florens L, Guan T, et al. Nuclear membrane proteins with potential disease links found by subtractive proteomics. Science. 2003;301(5638):1380–1382. PubMed

de Las Heras JI, Meinke P, Batrakou DG, et al. Tissue specificity in the nuclear envelope supports its functional complexity. Nucleus. 2013;4(6):460–477. PubMed PMC

Korfali N, Wilkie GS, Swanson SK, et al. The nuclear envelope proteome differs notably between tissues. Nucleus. 2012;3(6):552–564. PubMed PMC

Wilhelmsen K, Litjens SH, Kuikman I, et al. Nesprin-3, a novel outer nuclear membrane protein, associates with the cytoskeletal linker protein plectin. J Cell Biol. 2005;171(5):799–810. PubMed PMC

Brachner A, Reipert S, Foisner R, et al. LEM2 is a novel MAN1-related inner nuclear membrane protein associated with A-type lamins. J Cell Sci. 2005;118(24):5797–5810. PubMed

Rout MP, Field MC. Isolation and characterization of subnuclear compartments from Trypanosoma brucei. identification of a major repetitive nuclear lamina component. J Biol Chem. 2001;276(41):38261–38271. PubMed

DeGrasse JA, DuBois KN, Devos D, et al. Evidence for a shared nuclear pore complex architecture that is conserved from the last common eukaryotic ancestor. Mol Cell Proteomics. 2009;8(9):2119–2130. PubMed PMC

Sonnhammer EL, von Heijne G, Krogh A. A hidden markov model for predicting transmembrane helices in protein sequences. Proceedings International Conference on Intelligent Systems for Molecular Biology. 1998;6:175–182. PubMed

Aslett M, Aurrecoechea C, Berriman M, et al. TriTrypDB: a functional genomic resource for the trypanosomatidae. Nucleic Acids Res. 2010;38(suppl_1):D457–62. PubMed PMC

Altschul SF, Madden TL, Schaffer AA, et al. Gapped BLAST and PSI-BLAST: a new generation of protein database search programs. Nucleic Acids Res. 1997;25(17):3389–3402. PubMed PMC

Edgar RC. MUSCLE: multiple sequence alignment with high accuracy and high throughput. Nucleic Acids Res. 2004;32(5):1792–1797. PubMed PMC

Lawrence TJ, Kauffman KT, Amrine KC, et al. FAST: FAST analysis of sequences toolbox. Front Genet. 2015;6:172. PubMed PMC

Price MN, Dehal PS, Arkin AP. FastTree 2–approximately maximum-likelihood trees for large alignments. PLoS One. 2010;5(3):e9490. PubMed PMC

Huerta-Cepas J, Serra F, Bork P. ETE 3: reconstruction, analysis, and visualization of phylogenomic data. Mol Biol Evol. 2016;33(6):1635–1638. PubMed PMC

Larsson A. AliView: a fast and lightweight alignment viewer and editor for large datasets. Bioinformatics. 2014;30(22):3276–3278. PubMed PMC

Waterhouse AM, Procter JB, Martin DM, et al. 2–a multiple sequence alignment editor and analysis workbench. Bioinformatics. 2009;25(9):1189–1191. PubMed PMC

Field HI, Coulson RM, Field MC. An automated graphics tool for comparative genomics: the Coulson plot generator. BMC Bioinf. 2013;14(1):141. PubMed PMC

UniProt C. UniProt: a worldwide hub of protein knowledge. Nucleic Acids Res. 2019;47(D1):D506–D15. PubMed PMC

Huntley RP, Sawford T, Mutowo-Meullenet P, et al. The GOA database: gene ontology annotation updates for 2015. Nucleic Acids Res. 2015;43(D1):D1057–63. PubMed PMC

Tang Y, Huang A, Gu Y. Global profiling of plant nuclear membrane proteome in Arabidopsis. Nat Plants. 2020;6(7):838–847. PubMed

Graumann K, Evans DE. Growing the nuclear envelope proteome. Nat Plants. 2020;6(7):740–741. PubMed

Goos C, Dejung M, Janzen CJ, et al. The nuclear proteome of Trypanosoma brucei. PLoS One. 2017;12(7):e0181884. PubMed PMC

Dohmen E, Klasberg S, Bornberg-Bauer E, et al. The modular nature of protein evolution: domain rearrangement rates across eukaryotic life. BMC Evol Biol. 2020;20(1):30. PubMed PMC

Kawashima T, Kawashima S, Tanaka C, et al. Domain shuffling and the evolution of vertebrates. Genome Res. 2009;19(8):1393–1403. PubMed PMC

Burki F, Roger AJ, Brown MW, et al. The new tree of Eukaryotes. Trends Ecol Evol. 2020;35(1):43–55. PubMed

Ishikawa H, Barber GN. STING is an endoplasmic reticulum adaptor that facilitates innate immune signalling. Nature. 2008;455(7213):674–678. PubMed PMC

Malik P, Zuleger N, de Las Heras JI, et al. NET23/STING promotes chromatin compaction from the nuclear envelope. PLoS One. 2014;9(11):e111851. PubMed PMC

Datta K, Guan T, Gerace L. NET37, a nuclear envelope transmembrane protein with glycosidase homology, is involved in myoblast differentiation. J Biol Chem. 2009;284(43):29666–29676. PubMed PMC

Pall GS, Wallis J, Axton R, et al. A novel transmembrane MSP-containing protein that plays a role in right ventricle development. Genomics. 2004;84(6):1051–1059. PubMed

Muroyama Y, Saito T. Identification of Nepro, a gene required for the maintenance of neocortex neural progenitor cells downstream of Notch. Development. 2009;136(23):3889–3893. PubMed

Heyne K, Willnecker V, Schneider J, et al. NIR, an inhibitor of histone acetyltransferases, regulates transcription factor TAp63 and is controlled by the cell cycle. Nucleic Acids Res. 2010;38(10):3159–3171. PubMed PMC

Prieto JL, McStay B. Recruitment of factors linking transcription and processing of pre-rRNA to NOR chromatin is UBF-dependent and occurs independent of transcription in human cells. Genes Dev. 2007;21(16):2041–2054. PubMed PMC

Baillat D, Hakimi MA, Naar AM, et al. Integrator, a multiprotein mediator of small nuclear RNA processing, associates with the C-terminal repeat of RNA polymerase II. Cell. 2005;123(2):265–276. PubMed

Huang CY, Beliakoff J, Li X, et al. hZimp7, a novel PIAS-like protein, enhances androgen receptor-mediated transcription and interacts with SWI/SNF-like BAF complexes. Mol Endocrinol. 2005;19(12):2915–2929. PubMed

Ni Z, Olsen JB, Guo X, et al. Control of the RNA polymerase II phosphorylation state in promoter regions by CTD interaction domain-containing proteins RPRD1A and RPRD1B. Transcription. 2011;2(5):237–242. PubMed PMC

Ni Z, Xu C, Guo X, et al. RPRD1A and RPRD1B are human RNA polymerase II C-terminal domain scaffolds for Ser5 dephosphorylation. Nat Struct Mol Biol. 2014;21(8):686–695. PubMed PMC

Malik P, Korfali N, Srsen V, et al. Cell-specific and lamin-dependent targeting of novel transmembrane proteins in the nuclear envelope. Cell Mol Life Sci. 2010;67(8):1353–1369. PubMed PMC

Bronshtein I, Kepten E, Kanter I, et al. Loss of lamin A function increases chromatin dynamics in the nuclear interior. Nat Commun. 2015;6(1):8044. PubMed PMC

Moir RD, Yoon M, Khuon S, et al. Nuclear lamins A and B1: different pathways of assembly during nuclear envelope formation in living cells. J Cell Biol. 2000;151(6):1155–1168. PubMed PMC

Dechat T, Gesson K, Foisner R. Lamina-independent lamins in the nuclear interior serve important functions. Cold Spring Harbor Symposia on Quantitative Biology. 2010;75:533–543. PubMed

Fong KW, Leung JW, Li Y, et al. MTR120/KIAA1383, a novel microtubule-associated protein, promotes microtubule stability and ensures cytokinesis. J Cell Sci. 2013;126(3):825–837. PubMed PMC

Li C, Wei J, Li Y, et al. Transmembrane protein 214 (TMEM214) mediates endoplasmic reticulum stress-induced caspase 4 enzyme activation and apoptosis. J Biol Chem. 2013;288(24):17908–17917. PubMed PMC

Wilkie GS, Korfali N, Swanson SK, et al. Several novel nuclear envelope transmembrane proteins identified in skeletal muscle have cytoskeletal associations. Mol Cell Proteomics. 2011;10(1):M110.003129. PubMed PMC

Houstek J, Kmoch S, Zeman J. TMEM70 protein - a novel ancillary factor of mammalian ATP synthase. Biochim Biophys Acta. 2009;1787(5):529–532. PubMed

Kovalčíková J, Vrbacký M, Pecina P, et al. TMEM70 facilitates biogenesis of mammalian ATP synthase by promoting subunit c incorporation into the rotor structure of the enzyme. Faseb J. 2019;33(12):14103–14117. PubMed

Dacks JB, Field MC. Eukaryotic cell evolution from a comparative genomic perspective: the endomembrane system. In: Hirt RP, Horner DS, editors. Organelles, genomes and eukaryote phylogeny: an evolutionary synthesis in the age of genomics. CRC Press; 2004;309–334.

Te Heesen S, Knauer R, Lehle L, et al. Yeast Wbp1p and Swp1p form a protein complex essential for oligosaccharyl transferase activity. Embo J. 1993;12(1):279–284. PubMed PMC

Te Heesen S, Rauhut R, Aebersold R, et al. An essential 45 kDa yeast transmembrane protein reacts with anti-nuclear pore antibodies: purification of the protein, immunolocalization and cloning of the gene. Eur J Cell Biol. 1991;56(1):8–18. PubMed

Howe AG, Zaremberg V, McMaster CR. Cessation of growth to prevent cell death due to inhibition of phosphatidylcholine synthesis is impaired at 37 degrees C in Saccharomyces cerevisiae. J Biol Chem. 2002;277(46):44100–44107. PubMed

Dean S, Sunter JD, Wheeler RJ. TrypTag.org: a trypanosome genome-wide protein localisation resource. Trends Parasitol. 2017;33(2):80–82. PubMed PMC

Garapati HS, Mishra K. Comparative genomics of nuclear envelope proteins. BMC Genomics. 2018;19(1):823. PubMed PMC

Meier I. LINCing the eukaryotic tree of life - towards a broad evolutionary comparison of nucleocytoplasmic bridging complexes. J Cell Sci. 2016;129(19):3523–3531. PubMed

Zhou X, Graumann K, Wirthmueller L, et al. Identification of unique SUN-interacting nuclear envelope proteins with diverse functions in plants. J Cell Biol. 2014;205(5):677–692. PubMed PMC

Muchir A, Worman HJ. The nuclear envelope and human disease. Physiology (Bethesda). 2004;19:309–314. PubMed

Dauer WT, Worman HJ. The nuclear envelope as a signaling node in development and disease. Dev Cell. 2009;17(5):626–638. PubMed

Meinke P, Makarov A, Lê Thành P, et al. Nucleoskeleton dynamics and functions in health and disease. Cell Health and Cytoskeleton. 2014;7:55–69.

Zheng G, Jiang C, Li Y, et al. TMEM43-S358L mutation enhances NF-kappaB-TGFbeta signal cascade in arrhythmogenic right ventricular dysplasia/cardiomyopathy. Protein Cell. 2019;10(2):104–119. PubMed PMC

Heller SA, Shih R, Kalra R, et al. Emery-Dreifuss muscular dystrophy. Muscle Nerve. 2020;61(4):436–448. PubMed PMC

Liang WC, Mitsuhashi H, Keduka E, et al. TMEM43 mutations in Emery-Dreifuss muscular dystrophy-related myopathy. Ann Neurol. 2011;69(6):1005–1013. PubMed

Muhammad Aslam MK, Sharma VK, Pandey S, et al. Identification of biomarker candidates for fertility in spermatozoa of crossbred bulls through comparative proteomics. Theriogenology. 2018;119:43–51. PubMed

Bengtsson L, Otto H. LUMA interacts with emerin and influences its distribution at the inner nuclear membrane. J Cell Sci. 2008;121(4):536–548. PubMed

Browman DT, Resek ME, Zajchowski LD, et al. Erlin-1 and erlin-2 are novel members of the prohibitin family of proteins that define lipid-raft-like domains of the ER. J Cell Sci. 2006;119(15):3149–3160. PubMed

Yildirim Y, Orhan EK, Iseri SA, et al. A frameshift mutation of ERLIN2 in recessive intellectual disability, motor dysfunction and multiple joint contractures. Hum Mol Genet. 2011;20(10):1886–1892. PubMed

Wu H, Li J, Guo E, et al. MiR-410 acts as a tumor suppressor in estrogen receptor-positive breast cancer cells by directly targeting ERLIN2 via the ERS pathway. Cell Physiol Biochem. 2018;48(2):461–474. PubMed

Gudise S, Figueroa RA, Lindberg R, et al. 1 is functionally associated with the LINC complex and A-type lamina networks. J Cell Sci. 2011;124(12):2077–2085. PubMed

Meinke P, Kerr ARW, Czapiewski R, et al. A multistage sequencing strategy pinpoints novel candidate alleles for Emery-Dreifuss muscular dystrophy and supports gene misregulation as its pathomechanism. EBioMedicine. 2020;51:102587. PubMed PMC

Worman HJ, Yuan J, Blobel G, et al. A lamin B receptor in the nuclear envelope. Proc Natl Acad Sci U S A. 1988;85(22):8531–8534. PubMed PMC

Tsai PL, Zhao C, Turner E, et al. B receptor is essential for cholesterol synthesis and perturbed by disease-causing mutations. Elife. 2016;5:5. PubMed PMC

Subramanian G, Chaudhury P, Malu K, et al. Lamin B receptor regulates the growth and maturation of myeloid progenitors via its sterol reductase domain: implications for cholesterol biosynthesis in regulating myelopoiesis. J Immunol. 2012;188(1):85–102. PubMed PMC

Schrick K, Mayer U, Horrichs A, et al. FACKEL is a sterol C-14 reductase required for organized cell division and expansion in Arabidopsis embryogenesis. Genes Dev. 2000;14(12):1471–1484. PubMed PMC

Wheeler MA, Davies JD, Zhang Q, et al. Distinct functional domains in nesprin-1alpha and nesprin-2beta bind directly to emerin and both interactions are disrupted in X-linked Emery-Dreifuss muscular dystrophy. Exp Cell Res. 2007;313(13):2845–2857. PubMed

Zhang Q, Bethmann C, Worth NF, et al. Nesprin-1 and −2 are involved in the pathogenesis of Emery Dreifuss muscular dystrophy and are critical for nuclear envelope integrity. Hum Mol Genet. 2007;16(23):2816–2833. PubMed

Zhou C, Rao L, Shanahan CM, et al. Nesprin-1/2: roles in nuclear envelope organisation, myogenesis and muscle disease. Biochem Soc Trans. 2018;46(2):311–320. PubMed

Koch AJ, Holaska JM. Emerin in health and disease. Semin Cell Dev Biol. 2014;29:95–106. PubMed PMC

Robson MI, de Las Heras JI, Czapiewski R, et al. Tissue-specific gene repositioning by muscle nuclear membrane proteins enhances repression of critical developmental genes during myogenesis. Mol Cell. 2016;62(6):834–847. PubMed PMC

Zuleger N, Boyle S, Kelly DA, et al. Specific nuclear envelope transmembrane proteins can promote the location of chromosomes to and from the nuclear periphery. Genome Biol. 2013;14(2):R14. PubMed PMC

de Las Heras JI, Zuleger N, Batrakou DG, et al. Tissue-specific NETs alter genome organization and regulation even in a heterologous system. Nucleus. 2017;8(1):81–97. PubMed PMC

Klinger CM, Ramirez-Macias I, Herman EK, et al. Resolving the homology-function relationship through comparative genomics of membrane-trafficking machinery and parasite cell biology. Mol Biochem Parasitol. 2016;209(1–2):88–103. PubMed PMC

Reinstein E, Drasinover V, Lotan R, et al. Mutations in ERGIC1 cause arthrogryposis multiplex congenita, neuropathic type. Clin Genet. 2018;93(1):160–163. PubMed

Wang FR, Wei YC, Han ZJ, et al. Aberrant DNA-PKcs and ERGIC1 expression may be involved in initiation of gastric cancer. World J Gastroenterol. 2017;23(33):6119–6127. PubMed PMC

Li Q, Liu X, Jin K, et al. NAT10 is upregulated in hepatocellular carcinoma and enhances mutant p53 activity. BMC Cancer. 2017;17(1):605. PubMed PMC

Balmus G, Larrieu D, Barros AC, et al. Targeting of NAT10 enhances healthspan in a mouse model of human accelerated aging syndrome. Nat Commun. 2018;9(1):1700. PubMed PMC

Larrieu D, Britton S, Demir M, et al. Chemical inhibition of NAT10 corrects defects of laminopathic cells. Science. 2014;344(6183):527–532. PubMed PMC

Barateau A, Vadrot N, Vicart P, et al. A novel lamin a mutant responsible for congenital muscular dystrophy causes distinct abnormalities of the cell nucleus. PLoS One. 2017;12(1):e0169189. PubMed PMC

Thiel C, Schwarz M, Peng J, et al. A new type of congenital disorders of glycosylation (CDG-Ii) provides new insights into the early steps of dolichol-linked oligosaccharide biosynthesis. J Biol Chem. 2003;278(25):22498–22505. PubMed

Cossins J, Belaya K, Hicks D, et al. Congenital myasthenic syndromes due to mutations in ALG2 and ALG14. Brain. 2013;136(3):944–956. PubMed PMC

Belaya K, Finlayson S, Slater CR, et al. Mutations in DPAGT1 cause a limb-girdle congenital myasthenic syndrome with tubular aggregates. Am J Hum Genet. 2012;91(1):193–201. PubMed PMC

Brant SR, Panhuysen CI, Nicolae D, et al. MDR1 Ala893 polymorphism is associated with inflammatory bowel disease. Am J Hum Genet. 2003;73(6):1282–1292. PubMed PMC

Seo J, Lee CR, Paeng JC, et al. Biallelic mutations in ABCB1 display recurrent reversible encephalopathy. Ann Clin Transl Neurol. 2020;7(8):1443–1449. PubMed PMC

Merner ND, Hodgkinson KA, Haywood AF, et al. Arrhythmogenic right ventricular cardiomyopathy type 5 is a fully penetrant, lethal arrhythmic disorder caused by a missense mutation in the TMEM43 gene. Am J Hum Genet. 2008;82(4):809–821. PubMed PMC

Dominguez F, Zorio E, Jimenez-Jaimez J, et al. Clinical characteristics and determinants of the phenotype in TMEM43 arrhythmogenic right ventricular cardiomyopathy type 5. Heart Rhythm. 2020;17(6):945–954. PubMed

Mukai T, Mori-Yoshimura M, Nishikawa A, et al. Emery-Dreifuss muscular dystrophy-related myopathy with TMEM43 mutations. Muscle Nerve. 2019;59(2):E5–E7. PubMed

Srivastava S, D’Amore A, Cohen JS, et al. Expansion of the genetic landscape of ERLIN2-related disorders. Ann Clin Transl Neurol. 2020;7(4):573–578. PubMed PMC

Thompson E, Abdalla E, Superti-Furga A, et al. Lamin B receptor-related disorder is associated with a spectrum of skeletal dysplasia phenotypes. Bone. 2019;120:354–363. PubMed

Best S, Salvati F, Kallo J, et al. Lamin B-receptor mutations in Pelger-Huet anomaly. Br J Haematol. 2003;123(3):542–544. PubMed

Blommaert E, Peanne R, Cherepanova NA, et al. Mutations in MAGT1 lead to a glycosylation disorder with a variable phenotype. Proc Natl Acad Sci U S A. 2019;116(20):9865–9870. PubMed PMC

Li FY, Chaigne-Delalande B, Su H, et al. XMEN disease: a new primary immunodeficiency affecting Mg2+ regulation of immunity against Epstein-Barr virus. Blood. 2014;123(14):2148–2152. PubMed PMC

Strom TM, Hortnagel K, Hofmann S, et al. Diabetes insipidus, diabetes mellitus, optic atrophy and deafness (DIDMOAD) caused by mutations in a novel gene (Wolframin) coding for a predicted transmembrane protein. Hum Mol Genet. 1998;7(13):2021–2028. PubMed

Inoue H, Tanizawa Y, Wasson J, et al. A gene encoding a transmembrane protein is mutated in patients with diabetes mellitus and optic atrophy (Wolfram syndrome). Nat Genet. 1998;20(2):143–148. PubMed

Sawada A, Takihara Y, Kim JY, et al. A congenital mutation of the novel gene LRRC8 causes agammaglobulinemia in humans. J Clin Invest. 2003;112(11):1707–1713. PubMed PMC

Gasull X, Castany M, Castellanos A, et al. The LRRC8-mediated volume-regulated anion channel is altered in glaucoma. Sci Rep. 2019;9(1):5392. PubMed PMC

Laurin N, Brown JP, Morissette J, et al. Recurrent mutation of the gene encoding sequestosome 1 (SQSTM1/p62) in Paget disease of bone. Am J Hum Genet. 2002;70(6):1582–1588. PubMed PMC

Fecto F, Yan J, Vemula SP, et al. SQSTM1 mutations in familial and sporadic amyotrophic lateral sclerosis. Arch Neurol. 2011;68(11):1440–1446. PubMed

Bucelli RC, Arhzaouy K, Pestronk A, et al. SQSTM1 splice site mutation in distal myopathy with rimmed vacuoles. Neurology. 2015;85(8):665–674. PubMed PMC

Salminen A, Kaarniranta K, Haapasalo A, et al. Emerging role of p62/sequestosome-1 in the pathogenesis of Alzheimer’s disease. Prog Neurobiol. 2012;96(1):87–95. PubMed

Gorello P, La Starza R, Di Giacomo D, et al. SQSTM1-NUP214: a new gene fusion in adult T-cell acute lymphoblastic leukemia. Haematologica. 2010;95(12):2161–2163. PubMed PMC

Cizkova A, Stranecky V, Mayr JA, et al. TMEM70 mutations cause isolated ATP synthase deficiency and neonatal mitochondrial encephalocardiomyopathy. Nat Genet. 2008;40(11):1288–1290. PubMed

Hellemans J, Preobrazhenska O, Willaert A, et al. Loss-of-function mutations in LEMD3 result in osteopoikilosis, Buschke-Ollendorff syndrome and melorheostosis. Nat Genet. 2004;36(11):1213–1218. PubMed

Gillard EF, Otsu K, Fujii J, et al. Polymorphisms and deduced amino acid substitutions in the coding sequence of the ryanodine receptor (RYR1) gene in individuals with malignant hyperthermia. Genomics. 1992;13(4):1247–1254. PubMed

Quane KA, Healy JM, Keating KE, et al. Mutations in the ryanodine receptor gene in central core disease and malignant hyperthermia. Nat Genet. 1993;5(1):51–55. PubMed

Zhang Y, Chen HS, Khanna VK, et al. A mutation in the human ryanodine receptor gene associated with central core disease. Nat Genet. 1993;5(1):46–50. PubMed

Monnier N, Ferreiro A, Marty I, et al. A homozygous splicing mutation causing a depletion of skeletal muscle RYR1 is associated with multi-minicore disease congenital myopathy with ophthalmoplegia. Hum Mol Genet. 2003;12(10):1171–1178. PubMed

Paez JG, Janne PA, Lee JC, et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science. 2004;304(5676):1497–1500. PubMed

Campbell P, Morton PE, Takeichi T, et al. Epithelial inflammation resulting from an inherited loss-of-function mutation in EGFR. J Invest Dermatol. 2014;134(10):2570–2578. PubMed PMC

Nagano A, Koga R, Ogawa M, et al. Emerin deficiency at the nuclear membrane in patients with Emery-Dreifuss muscular dystrophy. Nat Genet. 1996;12(3):254–259. PubMed

Agopian AJ, Mitchell LE, Glessner J, et al. Genome-wide association study of maternal and inherited loci for conotruncal heart defects. PLoS One. 2014;9(5):e96057. PubMed PMC

Boone PM, Yuan B, Gu S, et al. Hutterite-type cataract maps to chromosome 6p21.32-p21.31, cosegregates with a homozygous mutation in LEMD2, and is associated with sudden cardiac death. Mol Genet Genomic Med. 2016;4(1):77–94. PubMed PMC

Xin B, Platzer P, Fink SP, et al. Colon cancer secreted protein-2 (CCSP-2), a novel candidate serological marker of colon neoplasia. Oncogene. 2005;24(4):724–731. PubMed

Jeun M, Lee HJ, Park S, et al. A novel blood-based colorectal cancer diagnostic technology using electrical detection of colon cancer secreted protein-2. Adv Sci (Weinh). 2019;6(11):1802115. PubMed PMC

Vander Heyden AB, Naismith TV, Snapp EL, et al. LULL1 retargets TorsinA to the nuclear envelope revealing an activity that is impaired by the DYT1 dystonia mutation. Mol Biol Cell. 2009;20(11):2661–2672. PubMed PMC

Taylor MR, Slavov D, Gajewski A, et al. Thymopoietin (lamina-associated polypeptide 2) gene mutation associated with dilated cardiomyopathy. Hum Mutat. 2005;26(6):566–574. PubMed

Gros-Louis F, Dupre N, Dion P, et al. Mutations in SYNE1 lead to a newly discovered form of autosomal recessive cerebellar ataxia. Nat Genet. 2007;39(1):80–85. PubMed

Attali R, Warwar N, Israel A, et al. Mutation of SYNE-1, encoding an essential component of the nuclear lamina, is responsible for autosomal recessive arthrogryposis. Hum Mol Genet. 2009;18(18):3462–3469. PubMed

Brandt DT, Baarlink C, Kitzing TM, et al. SCAI acts as a suppressor of cancer cell invasion through the transcriptional control of beta1-integrin. Nat Cell Biol. 2009;11(5):557–568. PubMed

Lu D, Wu Y, Wang Y, et al. CREPT accelerates tumorigenesis by regulating the transcription of cell-cycle-related genes. Cancer Cell. 2012;21(1):92–104. PubMed

Batrakou DG, de Las Heras JI, Czapiewski R, et al. TMEM120A and B: nuclear envelope transmembrane proteins important for adipocyte differentiation. PLoS One. 2015;10(5):e0127712. PubMed PMC

Beaulieu-Laroche L, Christin M, Donoghue A, et al. TACAN is an ion channel involved in sensing mechanical pain. Cell. 2020;180(5):956–67.e17. PubMed

Han S, Bahmanyar S, Zhang P, et al. Nuclear envelope phosphatase 1-regulatory subunit 1 (formerly TMEM188) is the metazoan Spo7p ortholog and functions in the lipin activation pathway. J Biol Chem. 2012;287(5):3123–3137. PubMed PMC

Hu Z, Gomes I, Horrigan SK, et al. A novel nuclear protein, 5qNCA (LOC51780) is a candidate for the myeloid leukemia tumor suppressor gene on chromosome 5 band q31. Oncogene. 2001;20(47):6946–6954. PubMed

Bi X, Xu Y, Li T, et al. RNA targets ribogenesis factor WDR43 to chromatin for transcription and pluripotency control. Mol Cell. 2019;75(1):102–16.e9. PubMed

Yang Y, Cao J, Shi Y. Identification and characterization of a gene encoding human LPGAT1, an endoplasmic reticulum-associated lysophosphatidylglycerol acyltransferase. J Biol Chem. 2004;279(53):55866–55874. PubMed

Liu Y, Jesus AA, Marrero B, et al. Activated STING in a vascular and pulmonary syndrome. N Engl J Med. 2014;371(6):507–518. PubMed PMC

Goodchild RE, Kim CE, Dauer WT. Loss of the dystonia-associated protein TorsinA selectively disrupts the neuronal nuclear envelope. Neuron. 2005;48(6):923–932. PubMed

Bennati AM, Castelli M, Della Fazia MA, et al. Sterol dependent regulation of human TM7SF2 gene expression: role of the encoded 3beta-hydroxysterol delta14-reductase in human cholesterol biosynthesis. Biochim Biophys Acta. 2006;1761(7):677–685. PubMed

Zhou H, Clapham DE. Mammalian MagT1 and TUSC3 are required for cellular magnesium uptake and vertebrate embryonic development. Proc Natl Acad Sci U S A. 2009;106(37):15750–15755. PubMed PMC

Joung I, Strominger JL, Shin J. Molecular cloning of a phosphotyrosine-independent ligand of the p56lck SH2 domain. Proc Natl Acad Sci U S A. 1996;93(12):5991–5995. PubMed PMC

Groenestege WM, Thébault S, van der Wijst J, et al. Impaired basolateral sorting of pro-EGF causes isolated recessive renal hypomagnesemia. J Clin Invest. 2007;117(8):2260–2267. PubMed PMC

Martin C, Chapman KE, Seckl JR, et al. Partial cloning and differential expression of ryanodine receptor/calcium-release channel genes in human tissues including the hippocampus and cerebellum. Neuroscience. 1998;85(1):205–216. PubMed

Yee SW, Stecula A, Chien HC, et al. Unraveling the functional role of the orphan solute carrier, SLC22A24 in the transport of steroid conjugates through metabolomic and genome-wide association studies. PLoS Genetics. 2019;15(9):e1008208. PubMed PMC

Sengle G, Kobbe B, Morgelin M, et al. Identification and characterization of AMACO, a new member of the von willebrand factor A-like domain protein superfamily with a regulated expression in the kidney. J Biol Chem. 2003;278(50):50240–50249. PubMed

Zhang Q, Skepper JN, Yang F, et al. Nesprins: a novel family of spectrin-repeat-containing proteins that localize to the nuclear membrane in multiple tissues. J Cell Sci. 2001;114(Pt 24):4485–4498. PubMed

Taranum S, Sur I, Müller R, et al. Cytoskeletal interactions at the nuclear envelope mediated by nesprins. International Journal of Cell Biology. 2012;2012:736524. PubMed PMC

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