Biallelic variants in CTU2 cause DREAM-PL syndrome and impair thiolation of tRNA wobble U34
| Autor: | Valeria Capra, Emily Bryant, Sarah S. Barnett, Mais Hashem, Paul R. Mark, Hutton M. Kearney, Tarfa Al-Sheddi, Vincenzo Nigro, Marcello Scala, Niema Ibrahim, John Millichap, Christopher T Prevost, Egidio Spinelli, Ahmad Alhag, Andrea Accogli, Fatima Estwani, Mona M. Alenazi, Nour Ewida, Firdous Abdulwahab, Adila Al-Kindi, Eman Alobeid, Fowzan S. Alkuraya, Ranad Shaheen, Dragony Fu |
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| Přispěvatelé: | Shaheen, Ranad, Mark, Paul, Prevost, Christopher T, Alkindi, Adila, Alhag, Ahmad, Estwani, Fatima, Al-Sheddi, Tarfa, Alobeid, Eman, Alenazi, Mona M, Ewida, Nour, Ibrahim, Niema, Hashem, Mai, Abdulwahab, Firdou, Bryant, Emily M, Spinelli, Egidio, Millichap, John, Barnett, Sarah S, Kearney, Hutton M, Accogli, Andrea, Scala, Marcello, Capra, Valeria, Nigro, Vincenzo, Fu, Dragony, Alkuraya, Fowzan S |
| Rok vydání: | 2019 |
| Předmět: |
Male
ambiguous genitalia TRNA modification Genotype renal agenesi CTU2 uridine thiolation DNA Mutational Analysis Lissencephaly Wobble base pair Biology Severity of Illness Index 03 medical and health sciences Consanguinity RNA Transfer Genetics medicine Humans Abnormalities Multiple Genetic Predisposition to Disease microcephaly Amino Acid Sequence Allele Genetics (clinical) Alleles Genetic Association Studies 030304 developmental biology 0303 health sciences tRNA Methyltransferases Polydactyly 030305 genetics & heredity Facies Genetic Variation Sequence Analysis DNA Syndrome polydactyly medicine.disease Magnetic Resonance Imaging Radiography Phenotype Mutation Transfer RNA RNA splicing dysmorphic facie Allelic heterogeneity Female tRNA modification lissencephaly |
| Zdroj: | Human mutation. 40(11) |
| ISSN: | 1098-1004 |
| Popis: | The wobble position in the anticodon loop of tRNA is subject to numerous post-transcriptional modifications. In particular, thiolation of the wobble uridine has been shown to play an important role in codon-anticodon interactions. This modification is catalyzed by a highly conserved CTU1/CTU2 complex, disruption of which has been shown to cause abnormal phenotypes in yeast, worms and plants. We have previously suggested that a single founder splicing variant in human CTU2 causes a novel multiple congenital anomalies syndrome consisting of dysmorphic facies, renal agenesis, ambiguous genitalia, microcephaly, polydactyly, and lissencephaly (DREAM-PL). In this work, we describe five new patients with DREAM-PL phenotype and whose molecular analysis expands the allelic heterogeneity of the syndrome to five different alleles; four of which predict protein truncation. Functional characterization using patient-derived cells for each of these alleles, as well as the original founder allele; revealed a specific impairment of wobble uridine thiolation in all known thiol-containing tRNAs. Our data establish a recognizable CTU2-linked autosomal recessive syndrome in humans characterized by defective thiolation of the wobble uridine. The potential deleterious consequences for the translational efficiency and fidelity during development as a mechanism for pathogenicity represent an attractive target of future investigations. This article is protected by copyright. All rights reserved. |
| Databáze: | OpenAIRE |
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