PUS7 mutations impair pseudouridylation in humans and cause intellectual disability and microcephaly.

Autor: Shaheen R; Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia., Tasak M; Department of Biochemistry and Biophysics, Center for RNA Biology, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA., Maddirevula S; Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia., Abdel-Salam GMH; Clinical Genetics Department, Human Genetics and Genome Research Division, National Research Centre, Cairo, Egypt.; Human Cytogenetics Department, Human Genetics and Genome Research Division, National Research Centre, Cairo, Egypt., Sayed ISM; Oro-dental Genetics Department, Human Genetics and Genome Research Division, National Research Centre, Cairo, Egypt., Alazami AM; Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia., Al-Sheddi T; Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia., Alobeid E; Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia., Phizicky EM; Department of Biochemistry and Biophysics, Center for RNA Biology, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA. eric_phizicky@urmc.rochester.edu., Alkuraya FS; Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia. falkuraya@kfshrc.edu.sa.; Saudi Human Genome Program, King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia. falkuraya@kfshrc.edu.sa.; Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh, Saudi Arabia. falkuraya@kfshrc.edu.sa.
Jazyk: angličtina
Zdroj: Human genetics [Hum Genet] 2019 Mar; Vol. 138 (3), pp. 231-239. Date of Electronic Publication: 2019 Feb 18.
DOI: 10.1007/s00439-019-01980-3
Abstrakt: Pseudouridylation is the most common post-transcriptional modification, wherein uridine is isomerized into 5-ribosyluracil (pseudouridine, Ψ). The resulting increase in base stacking and creation of additional hydrogen bonds are thought to enhance RNA stability. Pseudouridine synthases are encoded in humans by 13 genes, two of which are linked to Mendelian diseases: PUS1 and PUS3. Very recently, PUS7 mutations were reported to cause intellectual disability with growth retardation. We describe two families in which two different homozygous PUS7 mutations (missense and frameshift deletion) segregate with a phenotype comprising intellectual disability and progressive microcephaly. Short stature and hearing loss were variable in these patients. Functional characterization of the two mutations confirmed that both result in decreased levels of Ψ 13 in tRNAs. Furthermore, the missense variant of the S. cerevisiae ortholog failed to complement the growth defect of S. cerevisiae pus7Δ trm8Δ mutants. Our results confirm that PUS7 is a bona fide Mendelian disease gene and expand the list of human diseases caused by impaired pseudouridylation.
Databáze: MEDLINE
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