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Human Genetics

, Volume 138, Issue 3, pp 231–239 | Cite as

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

  • Ranad Shaheen
  • Monika Tasak
  • Sateesh Maddirevula
  • Ghada M. H. Abdel-Salam
  • Inas S. M. Sayed
  • Anas M. Alazami
  • Tarfa Al-Sheddi
  • Eman Alobeid
  • Eric M. PhizickyEmail author
  • Fowzan S. AlkurayaEmail author
Original Investigation

Abstract

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 Ψ13 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.

Keywords

Pseudouridylation Microcephaly PUS7 

Notes

Acknowledgements

We thank the study family for their enthusiastic participation. We also thank Mais Hashem, Niema Ibrahim and Firdous Abdulwahab for their help in coordinating the recruitment of the families and the Sequencing and Genotyping Core Facilities at KFSHRC for their technical help. This work was supported by the King Salman Center for Disability Research (F.S.A.), the Saudi Human Genome Program (F.S.A.), and by National Institutes of Health grant GM052347 (E.M.P.). M.T. was partially supported by NIH Training Grant in Cellular, Biochemical, and Molecular Sciences GM068411.

Compliance with ethical standards

Conflict of interest

Authors declare no conflict of interest.

Supplementary material

439_2019_1980_MOESM1_ESM.docx (18 kb)
Supplementary material 1 (DOCX 18 KB)

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of GeneticsKing Faisal Specialist Hospital and Research CenterRiyadhSaudi Arabia
  2. 2.Department of Biochemistry and Biophysics, Center for RNA BiologyUniversity of Rochester School of Medicine and DentistryRochesterUSA
  3. 3.Clinical Genetics Department, Human Genetics and Genome Research DivisionNational Research CentreCairoEgypt
  4. 4.Human Cytogenetics Department, Human Genetics and Genome Research DivisionNational Research CentreCairoEgypt
  5. 5.Oro-dental Genetics Department, Human Genetics and Genome Research DivisionNational Research CentreCairoEgypt
  6. 6.Saudi Human Genome ProgramKing Abdulaziz City for Science and TechnologyRiyadhSaudi Arabia
  7. 7.Department of Anatomy and Cell Biology, College of MedicineAlfaisal UniversityRiyadhSaudi Arabia

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