{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T19:46:41Z","timestamp":1790192801018,"version":"4.1.0"},"reference-count":49,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2022,1,7]],"date-time":"2022-01-07T00:00:00Z","timestamp":1641513600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000062","name":"National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"publisher","award":["R01DK126759"],"award-info":[{"award-number":["R01DK126759"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clinical Genetics"],"published-print":{"date-parts":[[2022,3]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Recessive mutations in the genes encoding the four subunits of the tRNA splicing endonuclease complex (\n                    <jats:italic>TSEN54<\/jats:italic>\n                    ,\n                    <jats:italic>TSEN34<\/jats:italic>\n                    ,\n                    <jats:italic>TSEN15<\/jats:italic>\n                    , and\n                    <jats:italic>TSEN2<\/jats:italic>\n                    ) cause various forms of pontocerebellar hypoplasia, a disorder characterized by hypoplasia of the cerebellum and the pons, microcephaly, dysmorphisms, and other variable clinical features. Here, we report an intronic recessive founder variant in the gene\n                    <jats:italic>TSEN2<\/jats:italic>\n                    that results in abnormal splicing of the mRNA of this gene, in six individuals from four consanguineous families affected with microcephaly, multiple craniofacial malformations, radiological abnormalities of the central nervous system, and cognitive retardation of variable severity. Remarkably, unlike patients with previously described mutations in the components of the TSEN complex, all the individuals that we report developed atypical hemolytic uremic syndrome (aHUS) with thrombotic microangiopathy, microangiopathic hemolytic anemia, thrombocytopenia, proteinuria, severe hypertension, and end\u2010stage kidney disease (ESKD) early in life. Bulk RNA sequencing of peripheral blood cells of four affected individuals revealed abnormal tRNA transcripts, indicating an alteration of the tRNA biogenesis. Morpholino\u2010mediated skipping of exon 10 of\n                    <jats:italic>tsen2<\/jats:italic>\n                    in zebrafish produced phenotypes similar to human patients. Thus, we have identified a novel syndrome accompanied by aHUS suggesting the existence of a link between tRNA biology and vascular endothelium homeostasis, which we propose to name with the acronym TRACK syndrome (\n                    <jats:italic>T<\/jats:italic>\n                    SEN2\n                    <jats:italic>R<\/jats:italic>\n                    elated\n                    <jats:italic>A<\/jats:italic>\n                    typical hemolytic uremic syndrome,\n                    <jats:italic>C<\/jats:italic>\n                    raniofacial malformations,\n                    <jats:italic>K<\/jats:italic>\n                    idney failure).\n                  <\/jats:p>","DOI":"10.1111\/cge.14105","type":"journal-article","created":{"date-parts":[[2021,12,29]],"date-time":"2021-12-29T02:38:21Z","timestamp":1640745501000},"page":"346-358","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["A splice site mutation in the\n                    <scp>\n                      <i>TSEN2<\/i>\n                    <\/scp>\n                    causes a new syndrome with craniofacial and central nervous system malformations, and atypical hemolytic uremic syndrome"],"prefix":"10.1111","volume":"101","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3420-9756","authenticated-orcid":false,"given":"Nur","family":"Canpolat","sequence":"first","affiliation":[{"name":"Department of Pediatric Nephrology Istanbul University\u2010Cerrahpasa, Cerrahpasa Faculty of Medicine  Istanbul Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7581-2527","authenticated-orcid":false,"given":"Dingxiao","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Carver College of Medicine University of Iowa  Iowa City Iowa USA"},{"name":"Department of Vascular Surgery, Second Xiangya Hospital Central South University  Changsha Hunan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8423-3431","authenticated-orcid":false,"given":"Emine","family":"Atayar","sequence":"additional","affiliation":[{"name":"Nephrogenetics Laboratory, Department of Pediatric Nephrology Hacettepe University, Faculty of Medicine  Ankara Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2424-6959","authenticated-orcid":false,"given":"Seha","family":"Saygili","sequence":"additional","affiliation":[{"name":"Department of Pediatric Nephrology Istanbul University\u2010Cerrahpasa, Cerrahpasa Faculty of Medicine  Istanbul Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6765-2543","authenticated-orcid":false,"given":"Nazli Sila","family":"Kara","sequence":"additional","affiliation":[{"name":"Biostatistics and Medical Informatics Program, Faculty of Medicine, Graduate School of Health Sciences Acibadem Mehmet Ali Aydinlar University  Istanbul Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Trudi A.","family":"Westfall","sequence":"additional","affiliation":[{"name":"Department of Biology University of Iowa  Iowa City Iowa USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiong","family":"Ding","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Carver College of Medicine University of Iowa  Iowa City Iowa USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bartley J.","family":"Brown","sequence":"additional","affiliation":[{"name":"Center for Bioinformatics and Computational Biology University of Iowa  Iowa City Iowa USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Terry A.","family":"Braun","sequence":"additional","affiliation":[{"name":"Center for Bioinformatics and Computational Biology University of Iowa  Iowa City Iowa 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Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9620-5021","authenticated-orcid":false,"given":"Beyhan","family":"Tuysuz","sequence":"additional","affiliation":[{"name":"Department of Pediatric Genetics Istanbul University\u2010Cerrahpasa, Cerrahpasa Faculty of Medicine  Istanbul Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3419-1661","authenticated-orcid":false,"given":"Tugba","family":"Tastemel Ozturk","sequence":"additional","affiliation":[{"name":"Department of Pediatric Nephrology Hacettepe University Faculty of Medicine  Ankara Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5918-6204","authenticated-orcid":false,"given":"Lale","family":"Sever","sequence":"additional","affiliation":[{"name":"Department of Pediatric Nephrology Istanbul University\u2010Cerrahpasa, Cerrahpasa Faculty of Medicine  Istanbul 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