Insight into ALKBH8-related intellectual developmental disability based on the first pathogenic missense variant.

Autor: Maddirevula S; Department of Translational Genomics, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, 11211, Saudi Arabia., Alameer S; Department of Pediatrics, Ministry of the National Guard-Health Affairs, King Abdullah International Medical Research Center, King Saud Bin Abdulaziz University for Health Sciences, Jeddah, Saudi Arabia., Ewida N; Department of Translational Genomics, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, 11211, Saudi Arabia., de Sousa MML; Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, 7491, Trondheim, Norway., Bjørås M; Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, 7491, Trondheim, Norway., Vågbø CB; Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, 7491, Trondheim, Norway.; Proteomics and Modomics Experimental Core and St. Olavs Hospital Central Staff, Trondheim, Norway., Alkuraya FS; Department of Translational Genomics, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, 11211, Saudi Arabia. FAlKuraya@kfshrc.edu.sa.; Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh, 11533, Saudi Arabia. FAlKuraya@kfshrc.edu.sa.
Jazyk: angličtina
Zdroj: Human genetics [Hum Genet] 2022 Feb; Vol. 141 (2), pp. 209-215. Date of Electronic Publication: 2021 Nov 10.
DOI: 10.1007/s00439-021-02391-z
Abstrakt: ALKBH8 is a methyltransferase that modifies tRNAs by methylating the anticodon wobble uridine residue. The syndrome of ALKBH8-related intellectual developmental disability (MRT71) has thus far been reported solely in the context of homozygous truncating variants that cluster in the last exon. This raises interesting questions about the disease mechanism, because these variants are predicted to escape nonsense mediated decay and yet they appear to be loss of function. Furthermore, the limited class of reported variants complicates the future interpretation of missense variants in ALKBH8. Here, we report a consanguineous family in which two children with MRT71-compatible phenotype are homozygous for a novel missense variant in the methyltransferase domain. We confirm the pathogenicity of this variant by demonstrating complete absence of ALKBH8-dependent modifications in patient cells. Targeted proteomics analysis of ALKBH8 indicates that the variant does not lead to loss of ALKBH8 protein expression. This report adds to the clinical delineation of MRT71, confirms loss of function of ALKBH8 as the disease mechanism and expands the repertoire of its molecular lesions.
(© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)
Databáze: MEDLINE
Externí odkaz: