2. Academic Validation
  3. Recessive Truncating Mutations in ALKBH8 Cause Intellectual Disability and Severe Impairment of Wobble Uridine Modification

Recessive Truncating Mutations in ALKBH8 Cause Intellectual Disability and Severe Impairment of Wobble Uridine Modification

  • Am J Hum Genet. 2019 Jun 6;104(6):1202-1209. doi: 10.1016/j.ajhg.2019.03.026.
Dorota Monies 1,  Cathrine Broberg Vågbø 2,  Mohammad Al-Owain 3,  Suzan Alhomaidi 4,  Fowzan S Alkuraya 5
Affiliations

Affiliations

  • 1 Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia.
  • 2 Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim 7491, Norway.
  • 3 Department of Medical Genetics, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia; Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University Riyadh 11533, Saudi Arabia.
  • 4 Department of Pediatrics, King Saud Medical Complex, Riyadh 12746, Saudi Arabia.
  • 5 Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia; Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University Riyadh 11533, Saudi Arabia. Electronic address: falkuraya@kfshrc.edu.sa.
PMID: 31079898 DOI: 10.1016/j.ajhg.2019.03.026
Abstract

The wobble hypothesis was proposed to explain the presence of fewer tRNAs than possible codons. The wobble nucleoside position in the anticodon stem-loop undergoes a number of modifications that help maintain the efficiency and fidelity of translation. AlkB homolog 8 (ALKBH8) is an atypical member of the highly conserved AlkB family of dioxygenases and is involved in the formation of mcm5s2U, (S)-mchm5U, (R)-mchm5U, mcm5U, and mcm5Um at the anticodon wobble uridines of specific tRNAs. In two multiplex consanguineous families, we identified two homozygous truncating ALKBH8 mutations causing intellectual disability. Analysis of tRNA derived from affected individuals showed the complete absence of these modifications, consistent with the presumptive loss of function of the variants. Our results highlight the sensitivity of the brain to impaired wobble modification and expand the list of intellectual-disability syndromes caused by mutations in genes related to tRNA modification.

Keywords

5-carbamoylmethyl; 5-methoxycarbonylmethyl; anticodon stem-loop; tRNA modification; wobble residue.

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