PUBLICATION
A splice site mutation in the TSEN2 causes a new syndrome with craniofacial and central nervous system malformations, and atypical hemolytic uremic syndrome
- Authors
- Canpolat, N., Liu, D., Atayar, E., Saygili, S., Kara, N.S., Westfall, T.A., Ding, Q., Brown, B.J., Braun, T.A., Slusarski, D., Oguz, K.K., Ozluk, Y., Tuysuz, B., Tastemel Ozturk, T., Sever, L., Sezerman, O.U., Topaloglu, R., Caliskan, S., Attanasio, M., Ozaltin, F.
- ID
- ZDB-PUB-211230-53
- Date
- 2021
- Source
- Clinical genetics 101(3): 346-358 (Journal)
- Registered Authors
- Slusarski, Diane C.
- Keywords
- TSEN2, atypical hemolytic uremic syndrome, cranio-facial malformation, novel syndrome, tRNA splicing endonuclease
- MeSH Terms
-
- Animals
- Atypical Hemolytic Uremic Syndrome*/genetics
- Endonucleases/genetics
- Female
- Humans
- Male
- Microcephaly*/complications
- Mutation/genetics
- RNA, Transfer
- Zebrafish/genetics
- PubMed
- 34964109 Full text @ Clin. Genet.
Citation
Canpolat, N., Liu, D., Atayar, E., Saygili, S., Kara, N.S., Westfall, T.A., Ding, Q., Brown, B.J., Braun, T.A., Slusarski, D., Oguz, K.K., Ozluk, Y., Tuysuz, B., Tastemel Ozturk, T., Sever, L., Sezerman, O.U., Topaloglu, R., Caliskan, S., Attanasio, M., Ozaltin, F. (2021) 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. 101(3):346-358.
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). This article is protected by copyright. All rights reserved.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping