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Biallelic variants in CTU2 cause DREAM-PL syndrome and impair thiolation of tRNA wobble U34.
Hum Mutat 2019HM

Abstract

The wobble position in the anticodon loop of transfer ribonucleic acid (tRNA) is subject to numerous posttranscriptional 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 study, 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.

Authors+Show Affiliations

Department of Genetics, King Faisal Specialist Hospital and Research Center, Saudi Arabia.Spectrum Health Division of Medical Genetics, Grand Rapids, Michigan.Department of Biology, Center for RNA Biology, University of Rochester, Rochester, New York.Genetics Department, Sultan Qaboos University Hospital, Muscat, Oman.Department of Pediatrics, Specialized Medical Center Hospital, Riyadh, Saudi Arabia.Department of Pediatrics, Specialized Medical Center Hospital, Riyadh, Saudi Arabia.Department of Genetics, King Faisal Specialist Hospital and Research Center, Saudi Arabia.Department of Genetics, King Faisal Specialist Hospital and Research Center, Saudi Arabia.Department of Genetics, King Faisal Specialist Hospital and Research Center, Saudi Arabia.Department of Genetics, King Faisal Specialist Hospital and Research Center, Saudi Arabia.Department of Genetics, King Faisal Specialist Hospital and Research Center, Saudi Arabia.Department of Genetics, King Faisal Specialist Hospital and Research Center, Saudi Arabia.Department of Genetics, King Faisal Specialist Hospital and Research Center, Saudi Arabia.Epilepsy Center and Division of Neurology, Ann & Robert H Lurie Children's Hospital of Chicago, Chicago, Illinois. Center for Genetic Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois.Epilepsy Center and Division of Neurology, Ann & Robert H Lurie Children's Hospital of Chicago, Chicago, Illinois.Epilepsy Center and Division of Neurology, Ann & Robert H Lurie Children's Hospital of Chicago, Chicago, Illinois. Department of Pediatrics and Neurology, Northwestern University Feinberg School of Medicine, Chicago, Illinois.Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota.Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota.Pediatric Neurology and Muscular Diseases Unit, Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, Istituto Giannina Gaslini, University of Genoa, Genoa, Italy.Department of Neurosurgery, IRCCS Istituto Giannina Gaslini, Genoa, Italy. Pediatric Neurology and Muscular Diseases Unit, Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, Istituto Giannina Gaslini, University of Genoa, Genoa, Italy.Department of Neurosurgery, IRCCS Istituto Giannina Gaslini, Genoa, Italy.Telethon Institute of Genetics and Medicine, Pozzuoli, Naples, Italy. Department of Precision Medicine, University of Campania 'Luigi Vanvitelli', Naples, Italy.Department of Biology, Center for RNA Biology, University of Rochester, Rochester, New York.Department of Genetics, King Faisal Specialist Hospital and Research Center, Saudi Arabia. Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh, Saudi Arabia.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31301155

Citation

Shaheen, Ranad, et al. "Biallelic Variants in CTU2 Cause DREAM-PL Syndrome and Impair Thiolation of tRNA Wobble U34." Human Mutation, 2019.
Shaheen R, Mark P, Prevost CT, et al. Biallelic variants in CTU2 cause DREAM-PL syndrome and impair thiolation of tRNA wobble U34. Hum Mutat. 2019.
Shaheen, R., Mark, P., Prevost, C. T., AlKindi, A., Alhag, A., Estwani, F., ... Alkuraya, F. S. (2019). Biallelic variants in CTU2 cause DREAM-PL syndrome and impair thiolation of tRNA wobble U34. Human Mutation, doi:10.1002/humu.23870.
Shaheen R, et al. Biallelic Variants in CTU2 Cause DREAM-PL Syndrome and Impair Thiolation of tRNA Wobble U34. Hum Mutat. 2019 Jul 13; PubMed PMID: 31301155.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Biallelic variants in CTU2 cause DREAM-PL syndrome and impair thiolation of tRNA wobble U34. AU - Shaheen,Ranad, AU - Mark,Paul, AU - Prevost,Christopher T, AU - AlKindi,Adila, AU - Alhag,Ahmad, AU - Estwani,Fatima, AU - Al-Sheddi,Tarfa, AU - Alobeid,Eman, AU - Alenazi,Mona M, AU - Ewida,Nour, AU - Ibrahim,Niema, AU - Hashem,Mais, AU - Abdulwahab,Firdous, AU - Bryant,Emily M, AU - Spinelli,Egidio, AU - Millichap,John, AU - Barnett,Sarah S, AU - Kearney,Hutton M, AU - Accogli,Andrea, AU - Scala,Marcello, AU - Capra,Valeria, AU - Nigro,Vincenzo, AU - Fu,Dragony, AU - Alkuraya,Fowzan S, Y1 - 2019/07/13/ PY - 2019/03/04/received PY - 2019/07/07/revised PY - 2019/07/08/accepted PY - 2019/7/14/pubmed PY - 2019/7/14/medline PY - 2019/7/14/entrez KW - CTU2 KW - ambiguous genitalia KW - dysmorphic facies KW - lissencephaly KW - microcephaly KW - mutation KW - polydactyly KW - renal agenesis KW - tRNA modification KW - uridine thiolation JF - Human mutation JO - Hum. Mutat. N2 - The wobble position in the anticodon loop of transfer ribonucleic acid (tRNA) is subject to numerous posttranscriptional 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 study, 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. SN - 1098-1004 UR - https://www.unboundmedicine.com/medline/citation/31301155/Biallelic_Variants_in_CTU2_Cause_DREAM-PL_Syndrome_and_Impair_Thiolation_of_tRNA_Wobble_U34 L2 - https://doi.org/10.1002/humu.23870 DB - PRIME DP - Unbound Medicine ER -