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Ketogenic diet modifies ribosomal protein dysregulation in KMT2D Kabuki syndrome.
- Source :
-
EBioMedicine [EBioMedicine] 2024 Jun; Vol. 104, pp. 105156. Date of Electronic Publication: 2024 May 19. - Publication Year :
- 2024
-
Abstract
- Background: Kabuki syndrome (KS) is a genetic disorder caused by DNA mutations in KMT2D, a lysine methyltransferase that methylates histones and other proteins, and therefore modifies chromatin structure and subsequent gene expression. Ketones, derived from the ketogenic diet, are histone deacetylase inhibitors that can 'open' chromatin and encourage gene expression. Preclinical studies have shown that the ketogenic diet rescues hippocampal memory neurogenesis in mice with KS via the epigenetic effects of ketones.<br />Methods: Single-cell RNA sequencing and mass spectrometry-based proteomics were used to explore molecular mechanisms of disease in individuals with KS (n = 4) versus controls (n = 4).<br />Findings: Pathway enrichment analysis indicated that loss of function mutations in KMT2D are associated with ribosomal protein dysregulation at an RNA and protein level in individuals with KS (FDR <0.05). Cellular proteomics also identified immune dysregulation and increased abundance of other lysine modification and histone binding proteins, representing a potential compensatory mechanism. A 12-year-old boy with KS, suffering from recurrent episodes of cognitive decline, exhibited improved cognitive function and neuropsychological assessment performance after 12 months on the ketogenic diet, with concomitant improvement in transcriptomic ribosomal protein dysregulation.<br />Interpretation: Our data reveals that lysine methyltransferase deficiency is associated with ribosomal protein dysfunction, with secondary immune dysregulation. Diet and the production of bioactive molecules such as ketone bodies serve as a significant environmental factor that can induce epigenetic changes and improve clinical outcomes. Integrating transcriptomic, proteomic, and clinical data can define mechanisms of disease and treatment effects in individuals with neurodevelopmental disorders.<br />Funding: This study was supported by the Dale NHMRC Investigator Grant (APP1193648) (R.D), Petre Foundation (R.D), and The Sydney Children's Hospital Foundation/Kids Research Early and Mid-Career Researcher Grant (E.T).<br />Competing Interests: Declaration of interests The authors report no competing interests.<br /> (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)
- Subjects :
- Humans
Male
Child
Female
Neoplasm Proteins genetics
Neoplasm Proteins metabolism
Gene Expression Regulation
Mutation
Transcriptome
Abnormalities, Multiple
Diet, Ketogenic
Vestibular Diseases genetics
Vestibular Diseases metabolism
Vestibular Diseases diet therapy
Face abnormalities
Hematologic Diseases metabolism
Hematologic Diseases genetics
Hematologic Diseases etiology
Hematologic Diseases diet therapy
DNA-Binding Proteins genetics
DNA-Binding Proteins metabolism
Ribosomal Proteins genetics
Ribosomal Proteins metabolism
Proteomics methods
Subjects
Details
- Language :
- English
- ISSN :
- 2352-3964
- Volume :
- 104
- Database :
- MEDLINE
- Journal :
- EBioMedicine
- Publication Type :
- Academic Journal
- Accession number :
- 38768529
- Full Text :
- https://doi.org/10.1016/j.ebiom.2024.105156