{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,11]],"date-time":"2026-04-11T12:59:51Z","timestamp":1775912391954,"version":"3.50.1"},"reference-count":138,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2022,12,14]],"date-time":"2022-12-14T00:00:00Z","timestamp":1670976000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["BioEssays"],"published-print":{"date-parts":[[2023,2]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Transfer RNAs (tRNAs) represent the most abundant class of RNA molecules in the cell and are key players during protein synthesis and cellular homeostasis. Aberrations in the extensive tRNA biogenesis pathways lead to severe neurological disorders in humans. Mutations in the tRNA splicing endonuclease (TSEN) and its associated RNA kinase cleavage factor polyribonucleotide kinase subunit 1 (CLP1) cause pontocerebellar hypoplasia (PCH), a heterogeneous group of neurodegenerative disorders, that manifest as underdevelopment of specific brain regions typically accompanied by microcephaly, profound motor impairments, and child mortality. Recently, we demonstrated that mutations leading to specific PCH subtypes destabilize TSEN in vitro and cause imbalances of immature to mature tRNA ratios in patient\u2010derived cells. However, how tRNA processing defects translate to disease on a systems level has not been understood. Recent findings suggested that other cellular processes may be affected by mutations in TSEN\/CLP1 and obscure the molecular mechanisms of PCH emergence. Here, we review PCH disease models linked to the TSEN\/CLP1 machinery and discuss future directions to study neuropathogenesis.<\/jats:p>","DOI":"10.1002\/bies.202200130","type":"journal-article","created":{"date-parts":[[2022,12,15]],"date-time":"2022-12-15T01:42:37Z","timestamp":1671068557000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["What connects splicing of transfer RNA precursor molecules with pontocerebellar hypoplasia?"],"prefix":"10.1002","volume":"45","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6732-9236","authenticated-orcid":false,"given":"Samoil","family":"Sekulovski","sequence":"first","affiliation":[{"name":"Institute of Biochemistry, Biocenter Goethe University Frankfurt  Frankfurt\/Main Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9143-766X","authenticated-orcid":false,"given":"Simon","family":"Trowitzsch","sequence":"additional","affiliation":[{"name":"Institute of Biochemistry, Biocenter Goethe University Frankfurt  Frankfurt\/Main Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2022,12,14]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00109\u2010021\u201002167\u2010y"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1242\/dmm.030205"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1242\/dmm.028613"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev\u2010genom\u2010083118\u2010015334"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/0022\u2010510x(90)90096\u20106"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/0387\u20107604(93)90080\u2010r"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.c.31403"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13023\u2010018\u20100826\u20102"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1186\/1750\u20101172\u20109\u201070"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.204"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0b013e3181f88173"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awq287"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/ejhg.2011.8"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1186\/1750\u20101172\u20106\u201050"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmg.2013.03.009"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2014.02.058"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2014.03.049"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2014.12.015"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2016.08.009"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12311\u2010020\u201001135\u20105"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.31095"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.3390\/brainsci11060746"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature10523"},{"key":"e_1_2_8_25_1","doi-asserted-by":"publisher","DOI":"10.3389\/fgene.2015.00002"},{"key":"e_1_2_8_26_1","doi-asserted-by":"publisher","DOI":"10.1261\/rna.067736.118"},{"key":"e_1_2_8_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.sbi.2019.03.014"},{"key":"e_1_2_8_28_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41580\u2010021\u201000342\u20100"},{"key":"e_1_2_8_29_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkv1309"},{"key":"e_1_2_8_30_1","doi-asserted-by":"publisher","DOI":"10.1002\/wrna.1583"},{"key":"e_1_2_8_31_1","doi-asserted-by":"publisher","DOI":"10.1016\/s0092\u20108674(04)00342\u20103"},{"key":"e_1_2_8_32_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1197847"},{"key":"e_1_2_8_33_1","doi-asserted-by":"publisher","DOI":"10.1261\/rna.052944.115"},{"key":"e_1_2_8_34_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkz311"},{"key":"e_1_2_8_35_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkaa438"},{"key":"e_1_2_8_36_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467\u2010021\u201025870\u20103"},{"key":"e_1_2_8_37_1","doi-asserted-by":"publisher","DOI":"10.1016\/s0092\u20108674(00)80270\u20106"},{"key":"e_1_2_8_38_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2006.11.024"},{"key":"e_1_2_8_39_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0502350102"},{"key":"e_1_2_8_40_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gks826"},{"key":"e_1_2_8_41_1","doi-asserted-by":"publisher","DOI":"10.1093\/emboj\/19.21.5895"},{"key":"e_1_2_8_42_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature05777"},{"key":"e_1_2_8_43_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2014.04.005"},{"key":"e_1_2_8_44_1","doi-asserted-by":"publisher","DOI":"10.1261\/rna.061788.117"},{"key":"e_1_2_8_45_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature11923"},{"key":"e_1_2_8_46_1","doi-asserted-by":"publisher","DOI":"10.1002\/wrna.1255"},{"key":"e_1_2_8_47_1","doi-asserted-by":"publisher","DOI":"10.3389\/fbioe.2020.00136"},{"key":"e_1_2_8_48_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.aba9763"},{"key":"e_1_2_8_49_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2005.09.012"},{"key":"e_1_2_8_50_1","doi-asserted-by":"publisher","DOI":"10.1101\/gad.183004.111"},{"key":"e_1_2_8_51_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M114.634592"},{"key":"e_1_2_8_52_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2020429118"},{"key":"e_1_2_8_53_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586\u2010021\u201003819\u20102"},{"key":"e_1_2_8_54_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586\u2010021\u201003828\u20101"},{"key":"e_1_2_8_55_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.abm4805"},{"key":"e_1_2_8_56_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41594\u2010021\u201000714\u20102"},{"key":"e_1_2_8_57_1","doi-asserted-by":"publisher","DOI":"10.1002\/wrna.1717"},{"key":"e_1_2_8_58_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2010.05.017"},{"key":"e_1_2_8_59_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddr034"},{"key":"e_1_2_8_60_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymgme.2003.08.010"},{"key":"e_1_2_8_61_1","doi-asserted-by":"publisher","DOI":"10.1038\/35053516"},{"key":"e_1_2_8_62_1","doi-asserted-by":"publisher","DOI":"10.1016\/s0960\u20109822(01)00585\u20101"},{"key":"e_1_2_8_63_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnana.2017.00064"},{"key":"e_1_2_8_64_1","doi-asserted-by":"publisher","DOI":"10.1086\/521227"},{"key":"e_1_2_8_65_1","doi-asserted-by":"publisher","DOI":"10.1242\/bio.058928"},{"key":"e_1_2_8_66_1","doi-asserted-by":"publisher","DOI":"10.1177\/0883073812470002"},{"key":"e_1_2_8_67_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00335\u2010017\u20109723\u20106"},{"key":"e_1_2_8_68_1","doi-asserted-by":"publisher","DOI":"10.1128\/mcb.11.11.5410\u20105416.1991"},{"key":"e_1_2_8_69_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.94.15.7897"},{"key":"e_1_2_8_70_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0029139"},{"key":"e_1_2_8_71_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkr801"},{"key":"e_1_2_8_72_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkr800"},{"key":"e_1_2_8_73_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2110730118"},{"key":"e_1_2_8_74_1","doi-asserted-by":"publisher","DOI":"10.3109\/01677063.2014.881358"},{"key":"e_1_2_8_75_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrd.2016.245"},{"key":"e_1_2_8_76_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2013.05.029"},{"key":"e_1_2_8_77_1","doi-asserted-by":"publisher","DOI":"10.15252\/msb.20145508"},{"key":"e_1_2_8_78_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.stemcr.2014.05.020"},{"key":"e_1_2_8_79_1","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.4291"},{"key":"e_1_2_8_80_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1258096"},{"key":"e_1_2_8_81_1","doi-asserted-by":"publisher","DOI":"10.1007\/978\u20101\u20104939\u20109080\u20101_9"},{"key":"e_1_2_8_82_1","doi-asserted-by":"publisher","DOI":"10.3389\/fmolb.2022.888424"},{"key":"e_1_2_8_83_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnana.2011.00029"},{"key":"e_1_2_8_84_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature04103"},{"key":"e_1_2_8_85_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2012.02.052"},{"key":"e_1_2_8_86_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature18637"},{"key":"e_1_2_8_87_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586\u2010019\u20101506\u20107"},{"key":"e_1_2_8_88_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature12517"},{"key":"e_1_2_8_89_1","doi-asserted-by":"publisher","DOI":"10.1242\/dmm.039347"},{"key":"e_1_2_8_90_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41593\u2010020\u201000730\u20103"},{"key":"e_1_2_8_91_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainres.2020.146803"},{"key":"e_1_2_8_92_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.semcdb.2020.10.011"},{"key":"e_1_2_8_93_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2014.12.051"},{"key":"e_1_2_8_94_1","doi-asserted-by":"publisher","DOI":"10.1101\/2022.10.13.512020"},{"key":"e_1_2_8_95_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrm.2017.7"},{"key":"e_1_2_8_96_1","doi-asserted-by":"publisher","DOI":"10.1515\/nf\u20102019\u20100021"},{"key":"e_1_2_8_97_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.aav8130"},{"key":"e_1_2_8_98_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.abd5059"},{"key":"e_1_2_8_99_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev\u2010neuro\u2010091421\u2010125115"},{"key":"e_1_2_8_100_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1249749"},{"key":"e_1_2_8_101_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2020.07.023"},{"key":"e_1_2_8_102_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tig.2017.12.007"},{"key":"e_1_2_8_103_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2017.09.057"},{"key":"e_1_2_8_104_1","doi-asserted-by":"publisher","DOI":"10.1038\/jhg.2015.31"},{"key":"e_1_2_8_105_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.33531"},{"key":"e_1_2_8_106_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2009.07.006"},{"key":"e_1_2_8_107_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature10423"},{"key":"e_1_2_8_108_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41431\u2010018\u20100233\u20100"},{"key":"e_1_2_8_109_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467\u2010020\u201019919\u2010y"},{"key":"e_1_2_8_110_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41431\u2010020\u201000749\u2010x"},{"key":"e_1_2_8_111_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2017.07.010"},{"key":"e_1_2_8_112_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2017.07.015"},{"key":"e_1_2_8_113_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.2425"},{"key":"e_1_2_8_114_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3354"},{"key":"e_1_2_8_115_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/aww212"},{"key":"e_1_2_8_116_1","doi-asserted-by":"publisher","DOI":"10.15252\/emmm.201506159"},{"key":"e_1_2_8_117_1","doi-asserted-by":"publisher","DOI":"10.1111\/cge.13084"},{"key":"e_1_2_8_118_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2020.10.035"},{"key":"e_1_2_8_119_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2013.07.005"},{"key":"e_1_2_8_120_1","doi-asserted-by":"publisher","DOI":"10.1212\/NXG.0000000000000014"},{"key":"e_1_2_8_121_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000001523"},{"key":"e_1_2_8_122_1","doi-asserted-by":"publisher","DOI":"10.1136\/jmedgenet\u20102013\u2010101823"},{"key":"e_1_2_8_123_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddy423"},{"key":"e_1_2_8_124_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmg.2019.103704"},{"key":"e_1_2_8_125_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.2254"},{"key":"e_1_2_8_126_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00415\u2010013\u20106896\u20100"},{"key":"e_1_2_8_127_1","doi-asserted-by":"publisher","DOI":"10.1186\/1750\u20101172\u20109\u201023"},{"key":"e_1_2_8_128_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00415\u2010014\u20107457\u2010x"},{"key":"e_1_2_8_129_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0b013e31827f0f66"},{"key":"e_1_2_8_130_1","doi-asserted-by":"publisher","DOI":"10.3109\/01677063.2013.814651"},{"key":"e_1_2_8_131_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10048\u2010013\u20100371\u2010z"},{"key":"e_1_2_8_132_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms5287"},{"key":"e_1_2_8_133_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmg.2019.01.012"},{"key":"e_1_2_8_134_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2018.03.011"},{"key":"e_1_2_8_135_1","doi-asserted-by":"publisher","DOI":"10.1038\/s10038\u2010020\u201000853\u20102"},{"key":"e_1_2_8_136_1","doi-asserted-by":"publisher","DOI":"10.1111\/cge.13928"},{"key":"e_1_2_8_137_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2010.09.007"},{"key":"e_1_2_8_138_1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.22617"},{"key":"e_1_2_8_139_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3762"}],"container-title":["BioEssays"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/bies.202200130","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/bies.202200130","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/bies.202200130","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,21]],"date-time":"2023-08-21T02:32:46Z","timestamp":1692585166000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/bies.202200130"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,12,14]]},"references-count":138,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2023,2]]}},"alternative-id":["10.1002\/bies.202200130"],"URL":"https:\/\/doi.org\/10.1002\/bies.202200130","archive":["Portico"],"relation":{},"ISSN":["0265-9247","1521-1878"],"issn-type":[{"value":"0265-9247","type":"print"},{"value":"1521-1878","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,12,14]]},"assertion":[{"value":"2022-07-03","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-11-30","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-12-14","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"2200130"}}