Journal article
A splice site mutation in the TSEN2 causes a new syndrome with craniofacial and central nervous system malformations, and atypical hemolytic uremic syndrome
Clinical genetics, Vol.101(3), pp.346-358
12/28/2021
DOI: 10.1111/cge.14105
PMCID: PMC10357464
PMID: 34964109
Abstract
Recessive mutations in the genes encoding the four subunits of the tRNA splicing endonuclease complex (TSEN54, TSEN34, TSEN15, and TSEN2) 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 TSEN2 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-stage 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-mediated skipping of exon 10 of tsen2 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 (TSEN2 Related Atypical hemolytic uremic syndrome, Craniofacial malformations, Kidney failure).
Details
- Title: Subtitle
- A splice site mutation in the TSEN2 causes a new syndrome with craniofacial and central nervous system malformations, and atypical hemolytic uremic syndrome
- Creators
- Nur Canpolat - Department of Pediatric Nephrology, Istanbul University-Cerrahpasa, Cerrahpasa Faculty of Medicine, Istanbul, TurkeyDingxiao Liu - Department of Vascular Surgery, Second Xiangya Hospital, Central South University, Changsha, Hunan, ChinaEmine Atayar - Nephrogenetics Laboratory, Department of Pediatric Nephrology, Hacettepe University, Faculty of Medicine, Ankara, TurkeySeha Saygili - Department of Pediatric Nephrology, Istanbul University-Cerrahpasa, Cerrahpasa Faculty of Medicine, Istanbul, TurkeyNazli Sila Kara - Biostatistics and Medical Informatics Program, Faculty of Medicine, Graduate School of Health Sciences, Acibadem Mehmet Ali Aydinlar University, Istanbul, TurkeyTrudi A Westfall - Department of Biology, University of Iowa, Iowa City, Iowa, USAQiong Ding - Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USABartley J Brown - Center for Bioinformatics and Computational Biology, University of Iowa, Iowa City, Iowa, USATerry A Braun - Center for Bioinformatics and Computational Biology, University of Iowa, Iowa City, Iowa, USADiane Slusarski - Center for Bioinformatics and Computational Biology, University of Iowa, Iowa City, Iowa, USAKader Karli Oguz - Department of Radiology, Hacettepe University Faculty of Medicine, Ankara, TurkeyYasemin Ozluk - Department of Pathology, Istanbul University Faculty of Medicine, Istanbul, TurkeyBeyhan Tuysuz - Department of Pediatric Genetics, Istanbul University-Cerrahpasa, Cerrahpasa Faculty of Medicine, Istanbul, TurkeyTugba Tastemel Ozturk - Department of Pediatric Nephrology, Hacettepe University Faculty of Medicine, Ankara, TurkeyLale Sever - Department of Pediatric Nephrology, Istanbul University-Cerrahpasa, Cerrahpasa Faculty of Medicine, Istanbul, TurkeyOsman Ugur Sezerman - Biostatistics and Medical Informatics Program, Faculty of Medicine, Graduate School of Health Sciences, Acibadem Mehmet Ali Aydinlar University, Istanbul, TurkeyRezan Topaloglu - Department of Pediatric Nephrology, Hacettepe University Faculty of Medicine, Ankara, TurkeySalim Caliskan - Department of Pediatric Nephrology, Istanbul University-Cerrahpasa, Cerrahpasa Faculty of Medicine, Istanbul, TurkeyMassimo Attanasio - Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USAFatih Ozaltin - Department of Pediatric Nephrology, Hacettepe University Faculty of Medicine, Ankara, Turkey
- Resource Type
- Journal article
- Publication Details
- Clinical genetics, Vol.101(3), pp.346-358
- DOI
- 10.1111/cge.14105
- PMID
- 34964109
- PMCID
- PMC10357464
- NLM abbreviation
- Clin Genet
- ISSN
- 0009-9163
- eISSN
- 1399-0004
- Grant note
- 3736-55436 / Scientific Research Projects Coordination Unit of Istanbul University-Cerrahpasa R01DK126759 / NIDDK NIH HHS 05-2019 / Turkish Pediatric Association
- Language
- English
- Date published
- 12/28/2021
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Iowa Neuroscience Institute; Biology; Fraternal Order of Eagles Diabetes Research Center; Dental Research; Internal Medicine
- Record Identifier
- 9984210346702771
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