{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T20:52:06Z","timestamp":1784235126256,"version":"3.55.0"},"reference-count":34,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2023,11,2]],"date-time":"2023-11-02T00:00:00Z","timestamp":1698883200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001265","name":"Academy of Medical Royal Colleges","doi-asserted-by":"publisher","award":["MR\/W024128\/1"],"award-info":[{"award-number":["MR\/W024128\/1"]}],"id":[{"id":"10.13039\/501100001265","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100019032","name":"Regionala Forskningsr\u00e5det Uppsala\/\u00d6rebro","doi-asserted-by":"publisher","award":["RFR\u2010649321"],"award-info":[{"award-number":["RFR\u2010649321"]}],"id":[{"id":"10.13039\/100019032","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Molec Gen &amp;amp; Gen Med"],"published-print":{"date-parts":[[2024,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Microcephaly with early\u2010onset seizures (MCSZ) is a neurodevelopmental disorder caused by pathogenic variants in the DNA strand break repair protein, polynucleotide kinase 3\u2032\u2010phosphatase (PNKP).<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We have used whole genome sequencing and Sanger sequencing to identify disease\u2010causing variants, followed by a minigene assay, Western blotting, alkaline comet assay, \u03b3H2AX, and ADP\u2010ribose immunofluorescence.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Here, we describe a patient with compound heterozygous variants in <jats:italic>PNKP<\/jats:italic>, including a missense variant in the DNA phosphatase domain (T323M) and a novel splice acceptor site variant within the DNA kinase domain that we show leads to exon skipping. We show that primary fibroblasts derived from the patient exhibit greatly reduced levels of PNKP protein and reduced rates of DNA single\u2010strand break repair, confirming that the mutated <jats:italic>PNKP<\/jats:italic> alleles are dysfunctional.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>The data presented show that the detected compound heterozygous variants result in reduced levels of PNKP protein, which affect the repair of both oxidative and TOP1\u2010induced single\u2010strand breaks, and most likely causes MCSZ in this patient.<\/jats:p><\/jats:sec>","DOI":"10.1002\/mgg3.2295","type":"journal-article","created":{"date-parts":[[2023,11,2]],"date-time":"2023-11-02T09:08:06Z","timestamp":1698916086000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Novel <scp>PNKP<\/scp> mutations associated with reduced <scp>DNA<\/scp> single\u2010strand break repair and severe microcephaly, seizures, and developmental delay"],"prefix":"10.1002","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4018-5551","authenticated-orcid":false,"given":"Ann\u2010Charlotte","family":"Thuresson","sequence":"first","affiliation":[{"name":"Department of Immunology, Genetics and Pathology, Science for Life Laboratory Uppsala Uppsala University  Uppsala Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan","family":"Brazina","sequence":"additional","affiliation":[{"name":"Genome Damage and Stability Centre University of Sussex  Brighton UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Talia","family":"Akram","sequence":"additional","affiliation":[{"name":"Department of Immunology, Genetics and Pathology, Science for Life Laboratory Uppsala Uppsala University  Uppsala Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia","family":"Albrecht","sequence":"additional","affiliation":[{"name":"Department of Pediatrics Falun Hospital  Falun Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Niklas","family":"Dahl","sequence":"additional","affiliation":[{"name":"Department of Immunology, Genetics and Pathology, Science for Life Laboratory Uppsala Uppsala University  Uppsala Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cecilia","family":"Soussi\u00a0Zander","sequence":"additional","affiliation":[{"name":"Department of Immunology, Genetics and Pathology, Science for Life Laboratory Uppsala Uppsala University  Uppsala Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keith W.","family":"Caldecott","sequence":"additional","affiliation":[{"name":"Genome Damage and Stability Centre University of Sussex  Brighton UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2023,11,2]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12185\u2010020\u201002950\u20106"},{"key":"e_1_2_12_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2005.02.012"},{"key":"e_1_2_12_4_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/7.3.793"},{"key":"e_1_2_12_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2015.01.005"},{"key":"e_1_2_12_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/s0076\u20106879(05)09024\u20105"},{"key":"e_1_2_12_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/s0092\u20108674(02)01247\u20103"},{"key":"e_1_2_12_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tcb.2022.04.010"},{"key":"e_1_2_12_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.dnarep.2018.05.002"},{"key":"e_1_2_12_10_1","doi-asserted-by":"publisher","DOI":"10.1093\/emboj\/21.11.2827"},{"key":"e_1_2_12_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymeth.2005.07.015"},{"key":"e_1_2_12_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature03314"},{"key":"e_1_2_12_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.braindev.2018.08.005"},{"key":"e_1_2_12_14_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.61339"},{"key":"e_1_2_12_15_1","doi-asserted-by":"publisher","DOI":"10.1136\/jmedgenet\u20102016\u2010103814"},{"key":"e_1_2_12_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature20790"},{"key":"e_1_2_12_17_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598\u2010022\u201009097\u2010w"},{"key":"e_1_2_12_18_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.274.34.24176"},{"key":"e_1_2_12_19_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkaa489"},{"key":"e_1_2_12_20_1","doi-asserted-by":"publisher","DOI":"10.1212\/nxg.0000000000000320"},{"key":"e_1_2_12_21_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.274.34.24187"},{"key":"e_1_2_12_22_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.emboj.7600375"},{"key":"e_1_2_12_23_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10048\u2010018\u20100555\u20107"},{"key":"e_1_2_12_24_1","doi-asserted-by":"publisher","DOI":"10.1111\/epi.14074"},{"key":"e_1_2_12_25_1","doi-asserted-by":"publisher","DOI":"10.4161\/cc.9.4.10764"},{"key":"e_1_2_12_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/s0092\u20108674(04)00206\u20105"},{"key":"e_1_2_12_27_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10048\u2010012\u20100351\u20108"},{"key":"e_1_2_12_28_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gks318"},{"key":"e_1_2_12_29_1","doi-asserted-by":"publisher","DOI":"10.1038\/gim.2015.30"},{"key":"e_1_2_12_30_1","doi-asserted-by":"publisher","DOI":"10.1055\/s\u20100039\u20101684008"},{"key":"e_1_2_12_31_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.526"},{"key":"e_1_2_12_32_1","doi-asserted-by":"publisher","DOI":"10.1111\/cge.13106"},{"key":"e_1_2_12_33_1","doi-asserted-by":"publisher","DOI":"10.1055\/s\u20100040\u20101710540"},{"key":"e_1_2_12_34_1","doi-asserted-by":"publisher","DOI":"10.1016\/s0092\u20108674(01)00195\u20107"},{"key":"e_1_2_12_35_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.b.32574"}],"container-title":["Molecular Genetics &amp; Genomic Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/mgg3.2295","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,1,29]],"date-time":"2024-01-29T12:26:47Z","timestamp":1706531207000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/mgg3.2295"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,11,2]]},"references-count":34,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2024,1]]}},"alternative-id":["10.1002\/mgg3.2295"],"URL":"https:\/\/doi.org\/10.1002\/mgg3.2295","archive":["Portico"],"relation":{},"ISSN":["2324-9269","2324-9269"],"issn-type":[{"value":"2324-9269","type":"print"},{"value":"2324-9269","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,11,2]]},"assertion":[{"value":"2023-03-16","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-09-19","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-11-02","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e2295"}}