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Author Notes:

Homa Ghalei, hghalei@emory.edu

R. E. D.-W., S. K., and H. G. conceptualization; R. E. D.-W., S. K., V. M., Y. M., and H. G. methodology; R. E. D.-W., S. K., V. M., Y. M., and H. G. validation; R. E. D.-W., L. N. C., S. K., V. M., Y. M., and H. G. formal analysis; R. E. D.-W., L. N. C., S. K., V. M., and H. G. investigation; R. E. D.-W. and H. G. writing-original draft; R. E. D.-W., L. N. C., S. K., Y. M., and H. G. writing-review & editing; R. E. D.-W., L. N. C., and H. G. visualization; S. K., Y. M., and H. G. supervision; V. M. data curation; Y. M. and H. G. resources; Y. M. and H. G. project administration; Y. M. and H. G. funding acquisition.

We thank Drs David Bedwell, John Dinman, Alan Hinnebusch, and Sunnie Thompson for the gift of plasmids. We also thank members of the Ghalei lab and Dr Anita Corbett for discussions and comments on the manuscript.

The authors declare that they have no conflicts of interest with the contents of this article.


Research Funding:

This work was supported by the National Institute of Health grant 1R35GM138123 and Emory University Research Committee (URC) Grant 00106132 (to H. G.) and by ANR grant MetRibo2020 and Région Grand Est FRCR grant EpiARN (to Y. M.).

R. E. D-W. was supported by an NSF Graduate Research Fellowship. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.


  • Science & Technology
  • Life Sciences & Biomedicine
  • Biochemistry & Molecular Biology
  • BOX-C/D

Studies of mutations of assembly factor Hit1 in budding yeast suggest translation defects as the molecular basis for PEHO syndrome


Journal Title:



Volume 298, Number 9


, Pages 102261-102261

Type of Work:

Article | Final Publisher PDF


Regulation of protein synthesis is critical for control of gene expression in all cells. Ribosomes are ribonucleoprotein machines responsible for translating cellular proteins. Defects in ribosome production, function, or regulation are detrimental to the cell and cause human diseases, such as progressive encephalopathy with edema, hypsarrhythmia, and optic atrophy (PEHO) syndrome. PEHO syndrome is a devastating neurodevelopmental disorder caused by mutations in the ZNHIT3 gene, which encodes an evolutionarily conserved nuclear protein. The precise mechanisms by which ZNHIT3 mutations lead to PEHO syndrome are currently unclear. Studies of the human zinc finger HIT-type containing protein 3 homolog in budding yeast (Hit1) revealed that this protein is critical for formation of small nucleolar ribonucleoprotein complexes that are required for rRNA processing and 2′-O-methylation. Here, we use budding yeast as a model system to reveal the basis for the molecular pathogenesis of PEHO syndrome. We show that missense mutations modeling those found in PEHO syndrome patients cause a decrease in steady-state Hit1 protein levels, a significant reduction of box C/D snoRNA levels, and subsequent defects in rRNA processing and altered cellular translation. Using RiboMethSeq analysis of rRNAs isolated from actively translating ribosomes, we reveal site-specific changes in the rRNA modification pattern of PEHO syndrome mutant yeast cells. Our data suggest that PEHO syndrome is a ribosomopathy and reveal potential new aspects of the molecular basis of this disease in translation dysregulation.

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© 2022 The Authors

This is an Open Access work distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).
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