Abstract
Nuclear speckles are small, membrane-less organelles that reside within the nucleus. Nuclear speckles serve as a regulatory hub coordinating complex RNA metabolism steps including gene transcription, pre-mRNA splicing, RNA modifications, and mRNA nuclear export. Reflecting the importance of proper nuclear speckle function in regulating normal human development, an increasing number of genetic disorders have been found to result from mutations in the genes encoding nuclear speckle proteins. To denote this growing class of genetic disorders, we propose “nuclear speckleopathies”. Notably, developmental disabilities are commonly seen in individuals with nuclear speckleopathies, suggesting the particular importance of nuclear speckles in ensuring normal neurocognitive development. In this review article, a general overview of nuclear speckle function, and the current knowledge of the mechanisms underlying some nuclear speckleopathies, such as ZTTK syndrome, NKAP-related syndrome, TARP syndrome, and TAR syndrome, are discussed. These nuclear speckleopathies represent valuable models to understand the basic function of nuclear speckles and how its functional defects result in human developmental disorders.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
Data availability
The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.
References
Albers CA, Paul DS, Schulze H, Freson K, Stephens JC, Smethurst PA, Jolley JD, Cvejic A, Kostadima M, Bertone P, Breuning MH, Debili N, Deloukas P, Favier R, Fiedler J, Hobbs CM, Huang N, Hurles ME, Kiddle G, Krapels I, Nurden P, Ruivenkamp CA, Sambrook JG, Smith K, Stemple DL, Strauss G, Thys C, van Geet C, Newbury-Ecob R, Ouwehand WH, Ghevaert C (2012) Compound inheritance of a low-frequency regulatory SNP and a rare null mutation in exon-junction complex subunit RBM8A causes TAR syndrome. Nat Genet 44(435–9):S1-2. https://doi.org/10.1038/ng.1083
Alexander KA, Cote A, Nguyen SC, Zhang L, Gholamalamdari O, Agudelo-Garcia P, Lin-Shiao E, Tanim KMA, Lim J, Biddle N, Dunagin MC, Good CR, Mendoza MR, Little SC, Belmont A, Joyce EF, Raj A, Berger SL (2021) p53 mediates target gene association with nuclear speckles for amplified RNA expression. Mol Cell 81:1666-1681 e6. https://doi.org/10.1016/j.molcel.2021.03.006
Barisic I, Odak L, Loane M, Garne E, Wellesley D, Calzolari E, Dolk H, Addor MC, Arriola L, Bergman J, Bianca S, Doray B, Khoshnood B, Klungsoyr K, McDonnell B, Pierini A, Rankin J, Rissmann A, Rounding C, Queisser-Luft A, Scarano G, Tucker D (2014) Prevalence, prenatal diagnosis and clinical features of oculo-auriculo-vertebral spectrum: a registry-based study in Europe. Eur J Hum Genet 22:1026–1033. https://doi.org/10.1038/ejhg.2013.287
Barutcu AR, Wu M, Braunschweig U, Dyakov BJA, Luo Z, Turner KM, Durbic T, Lin ZY, Weatheritt RJ, Maass PG, Gingras AC, Blencowe BJ (2022) Systematic mapping of nuclear domain-associated transcripts reveals speckles and lamina as hubs of functionally distinct retained introns. Mol Cell 82:1035-1052 e9. https://doi.org/10.1016/j.molcel.2021.12.010
Beauchamp MC, Alam SS, Kumar S, Jerome-Majewska LA (2020) Spliceosomopathies and neurocristopathies: two sides of the same coin? Dev Dyn 249:924–945. https://doi.org/10.1002/dvdy.183
Beck JS (1961) Variations in the morphological patterns of “autoimmune” nuclear fluorescence. Lancet 1:1203–1205. https://doi.org/10.1016/s0140-6736(61)91944-4
Beleza-Meireles A, Clayton-Smith J, Saraiva JM, Tassabehji M (2014) Oculo-auriculo-vertebral spectrum: a review of the literature and genetic update. J Med Genet 51:635–645. https://doi.org/10.1136/jmedgenet-2014-102476
Bernier FP, Caluseriu O, Ng S, Schwartzentruber J, Buckingham KJ, Innes AM, Jabs EW, Innis JW, Schuette JL, Gorski JL, Byers PH, Andelfinger G, Siu V, Lauzon J, Fernandez BA, McMillin M, Scott RH, Racher H, Majewski J, Nickerson DA, Shendure J, Bamshad MJ, Parboosingh JS, Consortium FC (2012) Haploinsufficiency of SF3B4, a component of the pre-mRNA spliceosomal complex, causes Nager syndrome. Am J Hum Genet 90:925–933. https://doi.org/10.1016/j.ajhg.2012.04.004
Berro R, Pedati C, Kehn-Hall K, Wu W, Klase Z, Even Y, Geneviere AM, Ammosova T, Nekhai S, Kashanchi F (2008) CDK13, a new potential human immunodeficiency virus type 1 inhibitory factor regulating viral mRNA splicing. J Virol 82:7155–7166. https://doi.org/10.1128/JVI.02543-07
Blencowe BJ, Bauren G, Eldridge AG, Issner R, Nickerson JA, Rosonina E, Sharp PA (2000) The SRm160/300 splicing coactivator subunits. RNA 6:111–120. https://doi.org/10.1017/s1355838200991982
Boulias K, Greer EL (2022) Biological roles of adenine methylation in RNA. Nat Rev Genet. https://doi.org/10.1038/s41576-022-00534-0
Burgute BD, Peche VS, Steckelberg AL, Glockner G, Gassen B, Gehring NH, Noegel AA (2014) NKAP is a novel RS-related protein that interacts with RNA and RNA binding proteins. Nucleic Acids Res 42:3177–3193. https://doi.org/10.1093/nar/gkt1311
Cajal S (1910) El nucleo de las celulas piramidales del cerebro humano y de algunos mamiferos. Trab Lab Invest Biol 8:27–62
Carter KC, Taneja KL, Lawrence JB (1991) Discrete nuclear domains of poly(A) RNA and their relationship to the functional organization of the nucleus. J Cell Biol 115:1191–1202. https://doi.org/10.1083/jcb.115.5.1191
Champion-Arnaud P, Reed R (1994) The prespliceosome components SAP 49 and SAP 145 interact in a complex implicated in tethering U2 snRNP to the branch site. Genes Dev 8:1974–1983. https://doi.org/10.1101/gad.8.16.1974
Chen D, Li Z, Yang Q, Zhang J, Zhai Z, Shu HB (2003) Identification of a nuclear protein that promotes NF-kappaB activation. Biochem Biophys Res Commun 310:720–724
Chen Y, Zhang Y, Wang Y, Zhang L, Brinkman EK, Adam SA, Goldman R, van Steensel B, Ma J, Belmont AS (2018) Mapping 3D genome organization relative to nuclear compartments using TSA-Seq as a cytological ruler. J Cell Biol 217:4025–4048. https://doi.org/10.1083/jcb.201807108
Chuang TW, Lee KM, Tarn WY (2015) Function and pathological implications of exon junction complex factor Y14. Biomolecules 5:343–355. https://doi.org/10.3390/biom5020343
Cuinat S, Nizon M, Isidor B, Stegmann A, van Jaarsveld RH, van Gassen KL, van der Smagt JJ, Volker-Touw CML, Holwerda SJB, Terhal PA, Schuhmann S, Vasileiou G, Khalifa M, Nugud AA, Yasaei H, Ousager LB, Brasch-Andersen C, Deb W, Besnard T, Simon MEH, Amsterdam KH, Verbeek NE, Matalon D, Dykzeul N, White S, Spiteri E, Devriendt K, Boogaerts A, Willemsen M, Brunner HG, Sinnema M, De Vries BBA, Gerkes EH, Pfundt R, Izumi K, Krantz ID, Xu ZL, Murrell JR, Valenzuela I, Cusco I, Rovira-Moreno E, Yang Y, Bizaoui V, Patat O, Faivre L, Tran-Mau-Them F, Vitobello A, Denomme-Pichon AS, Philippe C, Bezieau S, Cogne B (2022) Loss-of-function variants in SRRM2 cause a neurodevelopmental disorder. Genet Med 24:1774–1780. https://doi.org/10.1016/j.gim.2022.04.011
Czeschik JC, Voigt C, Alanay Y, Albrecht B, Avci S, Fitzpatrick D, Goudie DR, Hehr U, Hoogeboom AJ, Kayserili H, Simsek-Kiper PO, Klein-Hitpass L, Kuechler A, Lopez-Gonzalez V, Martin M, Rahmann S, Schweiger B, Splitt M, Wollnik B, Ludecke HJ, Zeschnigk M, Wieczorek D (2013) Clinical and mutation data in 12 patients with the clinical diagnosis of Nager syndrome. Hum Genet 132:885–898. https://doi.org/10.1007/s00439-013-1295-2
Dennis G Jr, Sherman BT, Hosack DA, Yang J, Gao W, Lane HC, Lempicki RA (2003) DAVID: database for annotation, visualization, and integrated discovery. Genome Biol 4:P3
Dias AP, Dufu K, Lei H, Reed R (2010) A role for TREX components in the release of spliced mRNA from nuclear speckle domains. Nat Commun 1:97. https://doi.org/10.1038/ncomms1103
Dingemans AJM, Truijen KMG, Kim JH, Alacam Z, Faivre L, Collins KM, Gerkes EH, van Haelst M, van de Laar I, Lindstrom K, Nizon M, Pauling J, Heropolitanska-Pliszka E, Plomp AS, Racine C, Sachdev R, Sinnema M, Skranes J, Veenstra-Knol HE, Verberne EA, Vulto-van Silfhout AT, Wilsterman MEF, Ahn EE, de Vries BBA, Vissers L (2022) Establishing the phenotypic spectrum of ZTTK syndrome by analysis of 52 individuals with variants in SON. Eur J Hum Genet 30:271–281. https://doi.org/10.1038/s41431-021-00960-4
Dopie J, Sweredoski MJ, Moradian A, Belmont AS (2020) Tyramide signal amplification mass spectrometry (TSA-MS) ratio identifies nuclear speckle proteins. J Cell Biol. https://doi.org/10.1083/jcb.201910207
Dujardin G, Lafaille C, de la Mata M, Marasco LE, Munoz MJ, Le Jossic-Corcos C, Corcos L, Kornblihtt AR (2014) How slow RNA polymerase II elongation favors alternative exon skipping. Mol Cell 54:683–690. https://doi.org/10.1016/j.molcel.2014.03.044
Even Y, Durieux S, Escande ML, Lozano JC, Peaucellier G, Weil D, Geneviere AM (2006) CDC2L5, a Cdk-like kinase with RS domain, interacts with the ASF/SF2-associated protein p32 and affects splicing in vivo. J Cell Biochem 99:890–904. https://doi.org/10.1002/jcb.20986
Fan Z, Devlin JR, Hogg SJ, Doyle MA, Harrison PF, Todorovski I, Cluse LA, Knight DA, Sandow JJ, Gregory G, Fox A, Beilharz TH, Kwiatkowski N, Scott NE, Vidakovic AT, Kelly GP, Svejstrup JQ, Geyer M, Gray NS, Vervoort SJ, Johnstone RW (2020) CDK13 cooperates with CDK12 to control global RNA polymerase II processivity. Sci Adv. https://doi.org/10.1126/sciadv.aaz5041
Fei J, Jadaliha M, Harmon TS, Li ITS, Hua B, Hao Q, Holehouse AS, Reyer M, Sun Q, Freier SM, Pappu RV, Prasanth KV, Ha T (2017) Quantitative analysis of multilayer organization of proteins and RNA in nuclear speckles at super resolution. J Cell Sci 130:4180–4192. https://doi.org/10.1242/jcs.206854
Fica SM, Oubridge C, Wilkinson ME, Newman AJ, Nagai K (2019) A human postcatalytic spliceosome structure reveals essential roles of metazoan factors for exon ligation. Science 363:710–714. https://doi.org/10.1126/science.aaw5569
Fiordaliso SK, Iwata-Otsubo A, Ritter AL, Quesnel-Vallieres M, Fujiki K, Nishi E, Hancarova M, Miyake N, Morton JEV, Lee S, Hackmann K, Bando M, Masuda K, Nakato R, Arakawa M, Bhoj E, Li D, Hakonarson H, Takeda R, Harr M, Keena B, Zackai EH, Okamoto N, Mizuno S, Ko JM, Valachova A, Prchalova D, Vlckova M, Pippucci T, Seiler C, Choi M, Matsumoto N, Di Donato N, Barash Y, Sedlacek Z, Shirahige K, Izumi K (2019) Missense mutations in NKAP cause a disorder of transcriptional regulation characterized by marfanoid habitus and cognitive impairment. Am J Hum Genet 105:987–995. https://doi.org/10.1016/j.ajhg.2019.09.009
Fong N, Kim H, Zhou Y, Ji X, Qiu J, Saldi T, Diener K, Jones K, Fu XD, Bentley DL (2014) Pre-mRNA splicing is facilitated by an optimal RNA polymerase II elongation rate. Genes Dev 28:2663–2676. https://doi.org/10.1101/gad.252106.114
Galganski L, Urbanek MO, Krzyzosiak WJ (2017) Nuclear speckles: molecular organization, biological function and role in disease. Nucleic Acids Res 45:10350–10368. https://doi.org/10.1093/nar/gkx759
Gorlin RJ, Cervenka J, Anderson RC, Sauk JJ, Bevis WD (1970) Robin’s syndrome. A probably X-linked recessive subvariety exhibiting persistence of left superior vena cava and atrial septal defect. Am J Dis Child 119:176–178
Greenleaf AL (2019) Human CDK12 and CDK13, multi-tasking CTD kinases for the new millenium. Transcription 10:91–110. https://doi.org/10.1080/21541264.2018.1535211
Greig JA, Nguyen TA, Lee M, Holehouse AS, Posey AE, Pappu RV, Jedd G (2020) Arginine-enriched mixed-charge domains provide cohesion for nuclear speckle condensation. Mol Cell 77:1237-1250 e4. https://doi.org/10.1016/j.molcel.2020.01.025
Guo YE, Manteiga JC, Henninger JE, Sabari BR, Dall’Agnese A, Hannett NM, Spille JH, Afeyan LK, Zamudio AV, Shrinivas K, Abraham BJ, Boija A, Decker TM, Rimel JK, Fant CB, Lee TI, Cisse II, Sharp PA, Taatjes DJ, Young RA (2019) Pol II phosphorylation regulates a switch between transcriptional and splicing condensates. Nature 572:543–548. https://doi.org/10.1038/s41586-019-1464-0
Hamilton MJ, Caswell RC, Canham N, Cole T, Firth HV, Foulds N, Heimdal K, Hobson E, Houge G, Joss S, Kumar D, Lampe AK, Maystadt I, McKay V, Metcalfe K, Newbury-Ecob R, Park SM, Robert L, Rustad CF, Wakeling E, Wilkie AOM, Study T, Twigg SRF, Suri M (2018) Heterozygous mutations affecting the protein kinase domain of CDK13 cause a syndromic form of developmental delay and intellectual disability. J Med Genet 55:28–38. https://doi.org/10.1136/jmedgenet-2017-104620
Hojland AT, Lolas I, Okkels H, Lautrup CK, Diness BR, Petersen MB, Nielsen IK (2018) First reported adult patient with TARP syndrome: a case report. Am J Med Genet A 176:2915–2918. https://doi.org/10.1002/ajmg.a.40638
Hu S, Lv P, Yan Z, Wen B (2019) Disruption of nuclear speckles reduces chromatin interactions in active compartments. Epigenetics Chromatin 12:43. https://doi.org/10.1186/s13072-019-0289-2
Ilik IA, Malszycki M, Lubke AK, Schade C, Meierhofer D, Aktas T (2020) SON and SRRM2 are essential for nuclear speckle formation. Elife 9. https://doi.org/10.7554/eLife.60579
Inoue A (2021) RBM10: Structure, functions, and associated diseases. Gene 783:145463. https://doi.org/10.1016/j.gene.2021.145463
Inoue A, Tsugawa K, Tokunaga K, Takahashi KP, Uni S, Kimura M, Nishio K, Yamamoto N, Honda K, Watanabe T, Yamane H, Tani T (2008) S1–1 nuclear domains: characterization and dynamics as a function of transcriptional activity. Biol Cell 100:523–535. https://doi.org/10.1042/BC20070142
Inoue A, Yamamoto N, Kimura M, Nishio K, Yamane H, Nakajima K (2014) RBM10 regulates alternative splicing. FEBS Lett 588:942–947. https://doi.org/10.1016/j.febslet.2014.01.052
Ji X, Zhou Y, Pandit S, Huang J, Li H, Lin CY, Xiao R, Burge CB, Fu XD (2013) SR proteins collaborate with 7SK and promoter-associated nascent RNA to release paused polymerase. Cell 153:855–868. https://doi.org/10.1016/j.cell.2013.04.028
Johnston JJ, Teer JK, Cherukuri PF, Hansen NF, Loftus SK, Center NIHIS, Chong K, Mullikin JC, Biesecker LG (2010) Massively parallel sequencing of exons on the X chromosome identifies RBM10 as the gene that causes a syndromic form of cleft palate. Am J Hum Genet 86:743–748. https://doi.org/10.1016/j.ajhg.2010.04.007
Johnston JJ, Sapp JC, Curry C, Horton M, Leon E, Cusmano-Ozog K, Dobyns WB, Hudgins L, Zackai E, Biesecker LG (2014) Expansion of the TARP syndrome phenotype associated with de novo mutations and mosaicism. Am J Med Genet A 164A:120–128. https://doi.org/10.1002/ajmg.a.36212
Kaeppler KE, Stetson RC, Lanpher BC, Collura CA (2018) Infant male with TARP syndrome: review of clinical features, prognosis, and commonalities with previously reported patients. Am J Med Genet A 176:2911–2914. https://doi.org/10.1002/ajmg.a.40645
Khan M, Hou S, Chen M, Lei H (2022) Mechanisms of RNA export and nuclear retention. Wiley Interdiscip Rev RNA. https://doi.org/10.1002/wrna.1755
Kim JH, Baddoo MC, Park EY, Stone JK, Park H, Butler TW, Huang G, Yan X, Pauli-Behn F, Myers RM, Tan M, Flemington EK, Lim ST, Ahn EY (2016a) SON and its alternatively spliced isoforms control MLL complex-mediated H3K4me3 and transcription of leukemia-associated genes. Mol Cell 61:859–873. https://doi.org/10.1016/j.molcel.2016.02.024
Kim JH, Shinde DN, Reijnders MRF, Hauser NS, Belmonte RL, Wilson GR, Bosch DGM, Bubulya PA, Shashi V, Petrovski S, Stone JK, Park EY, Veltman JA, Sinnema M, Stumpel C, Draaisma JM, Nicolai J, University of Washington Center for Mendelian G, Yntema HG, Lindstrom K, de Vries BBA, Jewett T, Santoro SL, Vogt J, Deciphering Developmental Disorders S, Bachman KK, Seeley AH, Krokosky A, Turner C, Rohena L, Hempel M, Kortum F, Lessel D, Neu A, Strom TM, Wieczorek D, Bramswig N, Laccone FA, Behunova J, Rehder H, Gordon CT, Rio M, Romana S, Tang S, El-Khechen D, Cho MT, McWalter K, Douglas G, Baskin B, Begtrup A, Funari T, Schoch K, Stegmann APA, Stevens SJC, Zhang DE, Traver D, Yao X, MacArthur DG, Brunner HG, Mancini GM, Myers RM, Owen LB, Lim ST, Stachura DL, Vissers L, Ahn EYE (2016b) De novo mutations in SON disrupt RNA splicing of genes essential for brain development and metabolism, causing an intellectual-disability syndrome. Am J Hum Genet 99:711–719. https://doi.org/10.1016/j.ajhg.2016.06.029
Kim J, Han KY, Khanna N, Ha T, Belmont AS (2019) Nuclear speckle fusion via long-range directional motion regulates speckle morphology after transcriptional inhibition. J Cell Sci. https://doi.org/10.1242/jcs.226563
Kim J, Venkata NC, Hernandez Gonzalez GA, Khanna N, Belmont AS (2020) Gene expression amplification by nuclear speckle association. J Cell Biol. https://doi.org/10.1083/jcb.201904046
Klopocki E, Schulze H, Strauss G, Ott CE, Hall J, Trotier F, Fleischhauer S, Greenhalgh L, Newbury-Ecob RA, Neumann LM, Habenicht R, Konig R, Seemanova E, Megarbane A, Ropers HH, Ullmann R, Horn D, Mundlos S (2007) Complex inheritance pattern resembling autosomal recessive inheritance involving a microdeletion in thrombocytopenia-absent radius syndrome. Am J Hum Genet 80:232–240. https://doi.org/10.1086/510919
Ko TK, Kelly E, Pines J (2001) CrkRS: a novel conserved Cdc2-related protein kinase that colocalises with SC35 speckles. J Cell Sci 114:2591–2603. https://doi.org/10.1242/jcs.114.14.2591
Kohler S, Gargano M, Matentzoglu N, Carmody LC, Lewis-Smith D, Vasilevsky NA, Danis D, Balagura G, Baynam G, Brower AM, Callahan TJ, Chute CG, Est JL, Galer PD, Ganesan S, Griese M, Haimel M, Pazmandi J, Hanauer M, Harris NL, Hartnett MJ, Hastreiter M, Hauck F, He Y, Jeske T, Kearney H, Kindle G, Klein C, Knoflach K, Krause R, Lagorce D, McMurry JA, Miller JA, Munoz-Torres MC, Peters RL, Rapp CK, Rath AM, Rind SA, Rosenberg AZ, Segal MM, Seidel MG, Smedley D, Talmy T, Thomas Y, Wiafe SA, Xian J, Yuksel Z, Helbig I, Mungall CJ, Haendel MA, Robinson PN (2021) The human phenotype ontology in 2021. Nucleic Acids Res 49:D1207–D1217. https://doi.org/10.1093/nar/gkaa1043
Kushary ST, Revah-Politi A, Barua S, Ganapathi M, Accogli A, Aggarwal V, Brunetti-Pierri N, Cappuccio G, Capra V, Fagerberg CR, Gazdagh G, Guzman E, Hadonou M, Harrison V, Havelund K, Iancu D, Kraus A, Lippa NC, Mansukhani M, McBrian D, McEntagart M, Pacio-Miguez M, Palomares-Bralo M, Pottinger C, Ruivenkamp CAL, Sacco O, Santen GWE, Santos-Simarro F, Scala M, Short J, Sorensen KP, Woods CG, DDD Study Consortium T, Anyane Yeboa K (2021) ZTTK syndrome: clinical and molecular findings of 15 cases and a review of the literature. Am J Med Genet A 185:3740–3753. https://doi.org/10.1002/ajmg.a.62445
Lamond AI, Spector DL (2003) Nuclear speckles: a model for nuclear organelles. Nat Rev Mol Cell Biol 4:605–612. https://doi.org/10.1038/nrm1172
Lee Y, Rio DC (2015) Mechanisms and regulation of alternative pre-mRNA splicing. Annu Rev Biochem 84:291–323. https://doi.org/10.1146/annurev-biochem-060614-034316
Lerner EA, Lerner MR, Janeway CA Jr, Steitz JA (1981) Monoclonal antibodies to nucleic acid-containing cellular constituents: probes for molecular biology and autoimmune disease. Proc Natl Acad Sci U S A 78:2737–2741. https://doi.org/10.1073/pnas.78.5.2737
Li W, Laishram RS, Anderson RA (2013) The novel poly(A) polymerase Star-PAP is a signal-regulated switch at the 3’-end of mRNAs. Adv Biol Regul 53:64–76. https://doi.org/10.1016/j.jbior.2012.10.004
Liang K, Gao X, Gilmore JM, Florens L, Washburn MP, Smith E, Shilatifard A (2015) Characterization of human cyclin-dependent kinase 12 (CDK12) and CDK13 complexes in C-terminal domain phosphorylation, gene transcription, and RNA processing. Mol Cell Biol 35:928–938. https://doi.org/10.1128/MCB.01426-14
Lin S, Coutinho-Mansfield G, Wang D, Pandit S, Fu XD (2008) The splicing factor SC35 has an active role in transcriptional elongation. Nat Struct Mol Biol 15:819–826. https://doi.org/10.1038/nsmb.1461
Liu J, Lu X, Zhang S, Yuan L, Sun Y (2022) Molecular Insights into mRNA Polyadenylation and Deadenylation. Int J Mol Sci. https://doi.org/10.3390/ijms231910985
Lu X, Goke J, Sachs F, Jacques PE, Liang H, Feng B, Bourque G, Bubulya PA, Ng HH (2013) SON connects the splicing-regulatory network with pluripotency in human embryonic stem cells. Nat Cell Biol 15:1141–1152. https://doi.org/10.1038/ncb2839
Lu H, Yu D, Hansen AS, Ganguly S, Liu R, Heckert A, Darzacq X, Zhou Q (2018) Phase-separation mechanism for C-terminal hyperphosphorylation of RNA polymerase II. Nature 558:318–323. https://doi.org/10.1038/s41586-018-0174-3
Marques F, Moreau JL, Peaucellier G, Lozano JC, Schatt P, Picard A, Callebaut I, Perret E, Geneviere AM (2000) A new subfamily of high molecular mass CDC2-related kinases with PITAI/VRE motifs. Biochem Biophys Res Commun 279:832–837. https://doi.org/10.1006/bbrc.2000.4042
Mellman DL, Gonzales ML, Song C, Barlow CA, Wang P, Kendziorski C, Anderson RA (2008) A PtdIns4,5P2-regulated nuclear poly(A) polymerase controls expression of select mRNAs. Nature 451:1013–1017. https://doi.org/10.1038/nature06666
Miyagawa R, Tano K, Mizuno R, Nakamura Y, Ijiri K, Rakwal R, Shibato J, Masuo Y, Mayeda A, Hirose T, Akimitsu N (2012) Identification of cis- and trans-acting factors involved in the localization of MALAT-1 noncoding RNA to nuclear speckles. RNA 18:738–751. https://doi.org/10.1261/rna.028639.111
Niceta M, Barresi S, Pantaleoni F, Capolino R, Dentici ML, Ciolfi A, Pizzi S, Bartuli A, Dallapiccola B, Tartaglia M, Digilio MC (2019) TARP syndrome: Long-term survival, anatomic patterns of congenital heart defects, differential diagnosis and pathogenetic considerations. Eur J Med Genet 62:103534. https://doi.org/10.1016/j.ejmg.2018.09.001
Nojima T, Rebelo K, Gomes T, Grosso AR, Proudfoot NJ, Carmo-Fonseca M (2018) RNA polymerase II phosphorylated on CTD serine 5 interacts with the spliceosome during Co-transcriptional splicing. Mol Cell 72:369-379 e4. https://doi.org/10.1016/j.molcel.2018.09.004
O’Keefe RT, Mayeda A, Sadowski CL, Krainer AR, Spector DL (1994) Disruption of pre-mRNA splicing in vivo results in reorganization of splicing factors. J Cell Biol 124:249–260. https://doi.org/10.1083/jcb.124.3.249
Pajerowski AG, Nguyen C, Aghajanian H, Shapiro MJ, Shapiro VS (2009) NKAP is a transcriptional repressor of notch signaling and is required for T cell development. Immunity 30:696–707. https://doi.org/10.1016/j.immuni.2009.02.011
Pajerowski AG, Shapiro MJ, Gwin K, Sundsbak R, Nelson-Holte M, Medina K, Shapiro VS (2010) Adult hematopoietic stem cells require NKAP for maintenance and survival. Blood 116:2684–2693. https://doi.org/10.1182/blood-2010-02-268391
Petit F, Escande F, Jourdain AS, Porchet N, Amiel J, Doray B, Delrue MA, Flori E, Kim CA, Marlin S, Robertson SP, Manouvrier-Hanu S, Holder-Espinasse M (2014) Nager syndrome: confirmation of SF3B4 haploinsufficiency as the major cause. Clin Genet 86:246–251. https://doi.org/10.1111/cge.12259
Quinodoz SA, Ollikainen N, Tabak B, Palla A, Schmidt JM, Detmar E, Lai MM, Shishkin AA, Bhat P, Takei Y, Trinh V, Aznauryan E, Russell P, Cheng C, Jovanovic M, Chow A, Cai L, McDonel P, Garber M, Guttman M (2018) Higher-order inter-chromosomal hubs shape 3D genome organization in the nucleus. Cell 174:744–75724. https://doi.org/10.1016/j.cell.2018.05.024
Ramanathan A, Robb GB, Chan SH (2016) mRNA capping: biological functions and applications. Nucleic Acids Res 44:7511–7526. https://doi.org/10.1093/nar/gkw551
Saitoh N, Spahr CS, Patterson SD, Bubulya P, Neuwald AF, Spector DL (2004) Proteomic analysis of interchromatin granule clusters. Mol Biol Cell 15:3876–3890. https://doi.org/10.1091/mbc.e04-03-0253
Sawada Y, Miura Y, Umeki K, Tamaoki T, Fujinaga K, Ohtaki S (2000) Cloning and characterization of a novel RNA-binding protein SRL300 with RS domains. Biochim Biophys Acta 1492:191–195. https://doi.org/10.1016/s0167-4781(00)00065-8
Schmidt U, Im KB, Benzing C, Janjetovic S, Rippe K, Lichter P, Wachsmuth M (2009) Assembly and mobility of exon-exon junction complexes in living cells. RNA 15:862–876. https://doi.org/10.1261/rna.1387009
Sharma A, Takata H, Shibahara K, Bubulya A, Bubulya PA (2010) Son is essential for nuclear speckle organization and cell cycle progression. Mol Biol Cell 21:650–663. https://doi.org/10.1091/mbc.E09-02-0126
Shopland LS, Johnson CV, Lawrence JB (2002) Evidence that all SC-35 domains contain mRNAs and that transcripts can be structurally constrained within these domains. J Struct Biol 140:131–139. https://doi.org/10.1016/s1047-8477(02)00507-5
Sifrim A, Hitz MP, Wilsdon A, Breckpot J, Turki SH, Thienpont B, McRae J, Fitzgerald TW, Singh T, Swaminathan GJ, Prigmore E, Rajan D, Abdul-Khaliq H, Banka S, Bauer UM, Bentham J, Berger F, Bhattacharya S, Bu’Lock F, Canham N, Colgiu IG, Cosgrove C, Cox H, Daehnert I, Daly A, Danesh J, Fryer A, Gewillig M, Hobson E, Hoff K, Homfray T, Study I, Kahlert AK, Ketley A, Kramer HH, Lachlan K, Lampe AK, Louw JJ, Manickara AK, Manase D, McCarthy KP, Metcalfe K, Moore C, Newbury-Ecob R, Omer SO, Ouwehand WH, Park SM, Parker MJ, Pickardt T, Pollard MO, Robert L, Roberts DJ, Sambrook J, Setchfield K, Stiller B, Thornborough C, Toka O, Watkins H, Williams D, Wright M, Mital S, Daubeney PE, Keavney B, Goodship J, Consortium UK, Abu-Sulaiman RM, Klaassen S, Wright CF, Firth HV, Barrett JC, Devriendt K, FitzPatrick DR, Brook JD, Deciphering Developmental Disorders S, Hurles ME (2016) Distinct genetic architectures for syndromic and nonsyndromic congenital heart defects identified by exome sequencing. Nat Genet 48:1060–1065. https://doi.org/10.1038/ng.3627
Spector DL, Lamond AI (2011) Nuclear speckles. Cold Spring Harb Perspect Biol. https://doi.org/10.1101/cshperspect.a000646
Spector DL, Schrier WH, Busch H (1983) Immunoelectron microscopic localization of snRNPs. Biol Cell 49:1–10. https://doi.org/10.1111/j.1768-322x.1984.tb00215.x
Spector DL, Fu XD, Maniatis T (1991) Associations between distinct pre-mRNA splicing components and the cell nucleus. EMBO J 10:3467–3481. https://doi.org/10.1002/j.1460-2075.1991.tb04911.x
Su JH, Zheng P, Kinrot SS, Bintu B, Zhuang X (2020) Genome-scale imaging of the 3D organization and transcriptional activity of chromatin. Cell 182:1641-1659 e26. https://doi.org/10.1016/j.cell.2020.07.032
Sun C (2020) The SF3b complex: splicing and beyond. Cell Mol Life Sci 77:3583–3595. https://doi.org/10.1007/s00018-020-03493-z
Swift H (1959) Studies on nuclear fine structure. Brookhaven Symp Biol 12:134–152
Takenouchi T, Miura K, Uehara T, Mizuno S, Kosaki K (2016) Establishing SON in 21q22.11 as a cause a new syndromic form of intellectual disability: possible contribution to Braddock-Carey syndrome phenotype. Am J Med Genet A 170:2587–2590. https://doi.org/10.1002/ajmg.a.37761
Thomas JD, Polaski JT, Feng Q, De Neef EJ, Hoppe ER, McSharry MV, Pangallo J, Gabel AM, Belleville AE, Watson J, Nkinsi NT, Berger AH, Bradley RK (2020) RNA isoform screens uncover the essentiality and tumor-suppressor activity of ultraconserved poison exons. Nat Genet 52:84–94. https://doi.org/10.1038/s41588-019-0555-z
Timberlake AT, Griffin C, Heike CL, Hing AV, Cunningham ML, Chitayat D, Davis MR, Doust SJ, Drake AF, Duenas-Roque MM, Goldblatt J, Gustafson JA, Hurtado-Villa P, Johns A, Karp N, Laing NG, Magee L, University of Washington Center for Mendelian G, Mullegama SV, Pachajoa H, Porras-Hurtado GL, Schnur RE, Slee J, Singer SL, Staffenberg DA, Timms AE, Wise CA, Zarante I, Saint-Jeannet JP, Luquetti DV (2021) Haploinsufficiency of SF3B2 causes craniofacial microsomia. Nat Commun 12:4680. https://doi.org/10.1038/s41467-021-24852-9
Tokita MJ, Braxton AA, Shao Y, Lewis AM, Vincent M, Kury S, Besnard T, Isidor B, Latypova X, Bezieau S, Liu P, Motter CS, Melver CW, Robin NH, Infante EM, McGuire M, El-Gharbawy A, Littlejohn RO, McLean SD, Bi W, Bacino CA, Lalani SR, Scott DA, Eng CM, Yang Y, Schaaf CP, Walkiewicz MA (2016) De Novo truncating variants in SON cause intellectual disability, congenital malformations, and failure to thrive. Am J Hum Genet 99:720–727. https://doi.org/10.1016/j.ajhg.2016.06.035
Ueda M, Matsuki T, Fukada M, Eda S, Toya A, Iio A, Tabata H, Nakayama A (2020) Knockdown of son, a mouse homologue of the ZTTK syndrome gene, causes neuronal migration defects and dendritic spine abnormalities. Mol Brain 13:80. https://doi.org/10.1186/s13041-020-00622-4
Uhlen M, Fagerberg L, Hallstrom BM, Lindskog C, Oksvold P, Mardinoglu A, Sivertsson A, Kampf C, Sjostedt E, Asplund A, Olsson I, Edlund K, Lundberg E, Navani S, Szigyarto CA, Odeberg J, Djureinovic D, Takanen JO, Hober S, Alm T, Edqvist PH, Berling H, Tegel H, Mulder J, Rockberg J, Nilsson P, Schwenk JM, Hamsten M, von Feilitzen K, Forsberg M, Persson L, Johansson F, Zwahlen M, von Heijne G, Nielsen J, Ponten F (2015) Proteomics. Tissue-based map of the human proteome. Science 347:1260419. https://doi.org/10.1126/science.1260419
Wang Y, Gogol-Doring A, Hu H, Frohler S, Ma Y, Jens M, Maaskola J, Murakawa Y, Quedenau C, Landthaler M, Kalscheuer V, Wieczorek D, Wang Y, Hu Y, Chen W (2013) Integrative analysis revealed the molecular mechanism underlying RBM10-mediated splicing regulation. EMBO Mol Med 5:1431–1442. https://doi.org/10.1002/emmm.201302663
Wang Z, Qin G, Zhao TC (2014) HDAC4: mechanism of regulation and biological functions. Epigenomics 6:139–150. https://doi.org/10.2217/epi.13.73
Wang LY, Xiao SJ, Kunimoto H, Tokunaga K, Kojima H, Kimura M, Yamamoto T, Yamamoto N, Zhao H, Nishio K, Tani T, Nakajima K, Sunami K, Inoue A (2021a) Sequestration of RBM10 in nuclear bodies: targeting sequences and biological significance. Int J Mol Sci. https://doi.org/10.3390/ijms221910526
Wang S, Bleeck A, Nadif Kasri N, Kleefstra T, van Rhijn JR, Schubert D (2021b) SETD1A mediated H3K4 methylation and its role in neurodevelopmental and neuropsychiatric disorders. Front Mol Neurosci 14:772000. https://doi.org/10.3389/fnmol.2021.772000
Worlitzer MM, Schwamborn JC (2014) The Notch co-repressor protein NKAP is highly expressed in adult mouse subventricular zone neural progenitor cells. Neuroscience 266:138–149. https://doi.org/10.1016/j.neuroscience.2014.02.019
Xu Q, Xiang Y, Wang Q, Wang L, Brind’Amour J, Bogutz AB, Zhang Y, Zhang B, Yu G, Xia W, Du Z, Huang C, Ma J, Zheng H, Li Y, Liu C, Walker CL, Jonasch E, Lefebvre L, Wu M, Lorincz MC, Li W, Li L, Xie W (2019) SETD2 regulates the maternal epigenome, genomic imprinting and embryonic development. Nat Genet 51:844–856. https://doi.org/10.1038/s41588-019-0398-7
Xu S, Lai SK, Sim DY, Ang WSL, Li HY, Roca X (2022) SRRM2 organizes splicing condensates to regulate alternative splicing. Nucleic Acids Res 50:8599–8614. https://doi.org/10.1093/nar/gkac669
Zhang X, Chen MH, Wu X, Kodani A, Fan J, Doan R, Ozawa M, Ma J, Yoshida N, Reiter JF, Black DL, Kharchenko PV, Sharp PA, Walsh CA (2016) Cell-type-specific alternative splicing governs cell fate in the developing cerebral cortex. Cell 166:1147–116215. https://doi.org/10.1016/j.cell.2016.07.025
Zhang L, Zhang Y, Chen Y, Gholamalamdari O, Wang Y, Ma J, Belmont AS (2020) TSA-seq reveals a largely conserved genome organization relative to nuclear speckles with small position changes tightly correlated with gene expression changes. Genome Res 31:251–264. https://doi.org/10.1101/gr.266239.120
Zhu X, Petrovski S, Xie P, Ruzzo EK, Lu YF, McSweeney KM, Ben-Zeev B, Nissenkorn A, Anikster Y, Oz-Levi D, Dhindsa RS, Hitomi Y, Schoch K, Spillmann RC, Heimer G, Marek-Yagel D, Tzadok M, Han Y, Worley G, Goldstein J, Jiang YH, Lancet D, Pras E, Shashi V, McHale D, Need AC, Goldstein DB (2015) Whole-exome sequencing in undiagnosed genetic diseases: interpreting 119 trios. Genet Med 17:774–781. https://doi.org/10.1038/gim.2014.191
Funding
This work was supported by Children’s Hospital of Philadelphia and Japan Society for the Promotion of Science Grant-in-Aid for Transformative Research Areas (A) 20H05940 and Grant-in-Aid for Scientific Research (C) 21K06833. The authors have no relevant financial or nonfinancial interests to disclose.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
On behalf of all authors, the corresponding author states that there is no conflict of interest.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Information
Below is the link to the electronic supplementary material.
439_2023_2540_MOESM5_ESM.docx
Supplementary Supplemental table 5: Top 20 frequent HPO terms associated with NS proteins identified by Dopie et al. file5 (DOCX 18 KB)
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Regan-Fendt, K.E., Izumi, K. Nuclear speckleopathies: developmental disorders caused by variants in genes encoding nuclear speckle proteins. Hum. Genet. 143, 529–544 (2024). https://doi.org/10.1007/s00439-023-02540-6
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00439-023-02540-6