{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,15]],"date-time":"2026-07-15T15:45:15Z","timestamp":1784130315343,"version":"3.55.0"},"reference-count":68,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2020,5,4]],"date-time":"2020-05-04T00:00:00Z","timestamp":1588550400000},"content-version":"vor","delay-in-days":3,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004895","name":"European Social Fund","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004895","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Ann Clin Transl Neurol"],"published-print":{"date-parts":[[2020,5]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Distal motor neuropathies with a genetic origin have a heterogeneous clinical presentation with overlapping features affecting distal nerves and including spinal muscular atrophies and amyotrophic lateral sclerosis. This indicates that their genetic background is heterogeneous.<\/jats:p><\/jats:sec><jats:sec><jats:title>Patient and methods<\/jats:title><jats:p>In this work, we have identified and characterized the genetic and molecular base of a patient with a distal sensorimotor neuropathy of unknown origin. For this study, we performed whole\u2010exome sequencing, molecular modelling, cloning and expression of mutant gene, and biochemical and cell biology analysis of the mutant protein.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>A novel homozygous recessive mutation in the human <jats:italic>VRK1<\/jats:italic> gene, coding for a chromatin kinase, causing a substitution (c.637T\u00a0&gt;\u00a0C; p.Tyr213His) in exon 8, was detected in a patient presenting since childhood a progressive distal sensorimotor neuropathy and spinal muscular atrophy syndrome, with normal intellectual development. Molecular modelling predicted this mutant VRK1 has altered the kinase activation loop by disrupting its interaction with the C\u2010terminal regulatory region. The p.Y213H mutant protein has a reduced kinase activity with different substrates, including histones H3 and H2AX, proteins involved in DNA damage responses, such as p53 and 53BP1, and coilin, the scaffold for Cajal bodies. The mutant VRK1(Y213H) protein is unable to rescue the formation of Cajal bodies assembled on coilin, in the absence of wild\u2010type VRK1.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>The VRK1(Y213H) mutant protein alters the activation loop, impairs the kinase activity of VRK1 causing a functional insufficiency that impairs the formation of Cajal bodies assembled on coilin, a protein that regulates SMN1 and Cajal body formation.<\/jats:p><\/jats:sec>","DOI":"10.1002\/acn3.51050","type":"journal-article","created":{"date-parts":[[2020,5,4]],"date-time":"2020-05-04T23:44:39Z","timestamp":1588635879000},"page":"808-818","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["VRK1 (Y213H) homozygous mutant impairs Cajal bodies in a hereditary case of distal motor neuropathy"],"prefix":"10.1002","volume":"7","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0263-7473","authenticated-orcid":false,"given":"Ana T.","family":"Marcos","sequence":"first","affiliation":[{"name":"Unidad de Gen\u00e9tica Instituto para el Estudio de la Biolog\u00eda de la Reproducci\u00f3n Humana (INEBIR) Sevilla Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8397-9952","authenticated-orcid":false,"given":"Elena","family":"Mart\u00edn\u2010Doncel","sequence":"additional","affiliation":[{"name":"Molecular Mechanisms of Cancer Program Instituto de Biolog\u00eda Molecular y Celular del C\u00e1ncer Consejo Superior de Investigaciones Cient\u00edficas (CSIC) Universidad de Salamanca Salamanca Spain"},{"name":"Instituto de Investigaci\u00f3n Biom\u00e9dica de Salamanca (IBSAL) Hospital Universitario de Salamanca Salamanca Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5691-5320","authenticated-orcid":false,"given":"Patricia","family":"Morej\u00f3n\u2010Garc\u00eda","sequence":"additional","affiliation":[{"name":"Molecular Mechanisms of Cancer Program Instituto de Biolog\u00eda Molecular y Celular del C\u00e1ncer Consejo Superior de Investigaciones Cient\u00edficas (CSIC) Universidad de Salamanca Salamanca Spain"},{"name":"Instituto de Investigaci\u00f3n Biom\u00e9dica de Salamanca (IBSAL) Hospital Universitario de Salamanca Salamanca Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0674-6423","authenticated-orcid":false,"given":"I\u00f1igo","family":"Marcos\u2010Alcalde","sequence":"additional","affiliation":[{"name":"Molecular Modelling Group Centro de Biolog\u00eda Molecular \u201cSevero Ochoa\u201d CSIC\u2010Universidad Aut\u00f3noma de Madrid, Cantoblanco Madrid Spain"},{"name":"School of Experimental Sciences Biosciences Research Institute Universidad Francisco de Vitoria Pozuelo de Alarc\u00f3n, Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3131-729X","authenticated-orcid":false,"given":"Paulino","family":"G\u00f3mez\u2010Puertas","sequence":"additional","affiliation":[{"name":"Molecular Modelling Group Centro de Biolog\u00eda Molecular \u201cSevero Ochoa\u201d CSIC\u2010Universidad Aut\u00f3noma de Madrid, Cantoblanco Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6103-9852","authenticated-orcid":false,"given":"Mar\u00eda","family":"Segura\u2010Puimedon","sequence":"additional","affiliation":[{"name":"Quantitative Genomic Medicine Laboratories, qGenomics Espluges de Llobregat Barcelona Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7141-1865","authenticated-orcid":false,"given":"Lluis","family":"Armengol","sequence":"additional","affiliation":[{"name":"Quantitative Genomic Medicine Laboratories, qGenomics Espluges de Llobregat Barcelona Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2362-2251","authenticated-orcid":false,"given":"Jos\u00e9 M.","family":"Navarro\u2010Pando","sequence":"additional","affiliation":[{"name":"Unidad de Gen\u00e9tica Instituto para el Estudio de la Biolog\u00eda de la Reproducci\u00f3n Humana (INEBIR) Sevilla Spain"},{"name":"C\u00e1tedra de Reproducci\u00f3n y Gen\u00e9tica Humana Facultad de Ciencias de la Salud Universidad Europea del Atl\u00e1ntico Santander Spain"},{"name":"Fundaci\u00f3n Universitaria Iberoamericana (FUNIBER) Barcelona Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8997-3025","authenticated-orcid":false,"given":"Pedro A.","family":"Lazo","sequence":"additional","affiliation":[{"name":"Molecular Mechanisms of Cancer Program Instituto de Biolog\u00eda Molecular y Celular del C\u00e1ncer Consejo Superior de Investigaciones Cient\u00edficas (CSIC) Universidad de Salamanca Salamanca Spain"},{"name":"Instituto de Investigaci\u00f3n Biom\u00e9dica de Salamanca (IBSAL) Hospital Universitario de Salamanca Salamanca Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2020,5,4]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1136\/jnnp-2011-300952"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1097\/WCO.0000000000000373"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1097\/WCO.0b013e32833e1765"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbagrm.2016.12.008"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbagrm.2019.04.004"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1101\/gad.908401"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/srep10543"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkl374"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0122348"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1093\/emboj\/cdg187"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1091\/mbc.e06-03-0247"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.126003"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1080\/15592294.2015.1028708"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00018-008-7587-3"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gks634"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.1136\/jnnp-2019-320717"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2009.07.006"},{"key":"e_1_2_11_19_1","first-page":"1491","article-title":"Mutations in VRK1 associated with complex motor and sensory axonal neuropathy plus microcephaly","volume":"70","author":"Gonzaga\u2010Jauregui C","year":"2013","journal-title":"JAMA Neurol"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.1097\/CND.0000000000000096"},{"key":"e_1_2_11_21_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000002813"},{"key":"e_1_2_11_22_1","doi-asserted-by":"publisher","DOI":"10.1002\/acn3.701"},{"key":"e_1_2_11_23_1","doi-asserted-by":"publisher","DOI":"10.1002\/mus.26779"},{"key":"e_1_2_11_24_1","doi-asserted-by":"publisher","DOI":"10.1038\/s10038-018-0553-5"},{"key":"e_1_2_11_25_1","doi-asserted-by":"publisher","DOI":"10.2169\/internalmedicine.2126-18"},{"issue":"15","key":"e_1_2_11_26_1","first-page":"P4.\u2010005","article-title":"Two cases of spinal muscular atrophy due to mutations in the VRK1 gene (P4.4\u2010005)","volume":"92","author":"Sung A","year":"2019","journal-title":"Neurology"},{"key":"e_1_2_11_27_1","doi-asserted-by":"publisher","DOI":"10.1038\/gim.2015.30"},{"key":"e_1_2_11_28_1","doi-asserted-by":"publisher","DOI":"10.5858\/arpa.2014-0250-CP"},{"key":"e_1_2_11_29_1","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth0410-248"},{"key":"e_1_2_11_30_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12864-016-2722-2"},{"key":"e_1_2_11_31_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M110.200162"},{"key":"e_1_2_11_32_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0023235"},{"key":"e_1_2_11_33_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1203709"},{"key":"e_1_2_11_34_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00018-018-2746-7"},{"key":"e_1_2_11_35_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-019-49821-7"},{"key":"e_1_2_11_36_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00775-013-0992-6"},{"key":"e_1_2_11_37_1","doi-asserted-by":"publisher","DOI":"10.1038\/srep28532"},{"key":"e_1_2_11_38_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.febslet.2014.01.040"},{"key":"e_1_2_11_39_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.virol.2004.08.013"},{"key":"e_1_2_11_40_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M112.353102"},{"key":"e_1_2_11_41_1","doi-asserted-by":"publisher","DOI":"10.1021\/ja0121639"},{"key":"e_1_2_11_42_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jprot.2011.08.019"},{"key":"e_1_2_11_43_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13046-019-1204-1"},{"key":"e_1_2_11_44_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00018-018-2811-2"},{"key":"e_1_2_11_45_1","doi-asserted-by":"publisher","DOI":"10.1080\/15476286.2016.1243649"},{"key":"e_1_2_11_46_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.cellbio.20.010403.103738"},{"key":"e_1_2_11_47_1","first-page":"129","article-title":"Un sencillo metodo de coloracion selectiva del reticulo protoplasmatico y sus efectos en los diversos organos nerviosos de vertebrados e invertebrados","volume":"2","author":"Ramon y Cajal S","year":"1903","journal-title":"Trab Lab Invest Biol"},{"key":"e_1_2_11_48_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddq508"},{"key":"e_1_2_11_49_1","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a000653"},{"key":"e_1_2_11_50_1","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.200104083"},{"key":"e_1_2_11_51_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddm192"},{"key":"e_1_2_11_52_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddz060"},{"key":"e_1_2_11_53_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2007.10.096"},{"key":"e_1_2_11_54_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/dds174"},{"key":"e_1_2_11_55_1","doi-asserted-by":"publisher","DOI":"10.1038\/cddis.2012.115"},{"key":"e_1_2_11_56_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.1998-14.2015"},{"key":"e_1_2_11_57_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-018-29215-x"},{"key":"e_1_2_11_58_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.biochem.7b01262"},{"key":"e_1_2_11_59_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pbio.1000521"},{"key":"e_1_2_11_60_1","doi-asserted-by":"publisher","DOI":"10.3389\/fgene.2015.00091"},{"key":"e_1_2_11_61_1","doi-asserted-by":"publisher","DOI":"10.1242\/bio.018804"},{"key":"e_1_2_11_62_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neurobiolaging.2012.04.005"},{"key":"e_1_2_11_63_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0925-4439(03)00038-3"},{"key":"e_1_2_11_64_1","doi-asserted-by":"publisher","DOI":"10.1212\/01.wnl.0000218304.02715.04"},{"key":"e_1_2_11_65_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2006.08.027"},{"key":"e_1_2_11_66_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tins.2009.11.001"},{"key":"e_1_2_11_67_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0705055104"},{"key":"e_1_2_11_68_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.1671-06.2006"},{"key":"e_1_2_11_69_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0006218"}],"container-title":["Annals of Clinical and Translational Neurology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Facn3.51050","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/acn3.51050","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/acn3.51050","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/acn3.51050","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,6]],"date-time":"2023-09-06T10:30:15Z","timestamp":1693996215000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/acn3.51050"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,5]]},"references-count":68,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2020,5]]}},"alternative-id":["10.1002\/acn3.51050"],"URL":"https:\/\/doi.org\/10.1002\/acn3.51050","archive":["Portico"],"relation":{},"ISSN":["2328-9503","2328-9503"],"issn-type":[{"value":"2328-9503","type":"print"},{"value":"2328-9503","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,5]]},"assertion":[{"value":"2020-02-08","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2020-03-31","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2020-05-04","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}