Ketogenic diet modifies ribosomal protein dysregulation in KMT2D Kabuki syndromeResearch in context

Erica Tsang; Velda X. Han; Chloe Flutter; Sarah Alshammery; Brooke A. Keating; Tracey Williams; Brian S. Gloss; Mark E. Graham; Nader Aryamanesh; Ignatius Pang; Melanie Wong; David Winlaw; Michael Cardamone; Shekeeb Mohammad; Wendy Gold; Shrujna Patel; Russell C. Dale

EBioMedicine (Jun 2024)

Ketogenic diet modifies ribosomal protein dysregulation in KMT2D Kabuki syndromeResearch in context

Erica Tsang,
Velda X. Han,
Chloe Flutter,
Sarah Alshammery,
Brooke A. Keating,
Tracey Williams,
Brian S. Gloss,
Mark E. Graham,
Nader Aryamanesh,
Ignatius Pang,
Melanie Wong,
David Winlaw,
Michael Cardamone,
Shekeeb Mohammad,
Wendy Gold,
Shrujna Patel,
Russell C. Dale

Affiliations

Erica Tsang: Kids Neuroscience Centre, The Children's Hospital at Westmead, Faculty of Medicine and Health, University of Sydney, NSW, Australia; The Children's Hospital at Westmead Clinical School, Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia
Velda X. Han: Kids Neuroscience Centre, The Children's Hospital at Westmead, Faculty of Medicine and Health, University of Sydney, NSW, Australia; Khoo Teck Puat-National University Children's Medical Institute, National University Health System, Singapore, Singapore; Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
Chloe Flutter: The Kabuki Syndrome Foundation – Volunteer, Northbrook, IL, USA
Sarah Alshammery: Kids Neuroscience Centre, The Children's Hospital at Westmead, Faculty of Medicine and Health, University of Sydney, NSW, Australia; The Children's Hospital at Westmead Clinical School, Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia
Brooke A. Keating: Kids Neuroscience Centre, The Children's Hospital at Westmead, Faculty of Medicine and Health, University of Sydney, NSW, Australia
Tracey Williams: Kids Rehab, The Children's Hospital at Westmead, Sydney, NSW, Australia
Brian S. Gloss: Westmead Research Hub, Westmead Institute for Medical Research, Westmead, NSW, Australia
Mark E. Graham: Biomedical Proteomics, Children's Medical Research Institute, The University of Sydney, Australia
Nader Aryamanesh: Bioinformatics Group, Children's Medical Research Institute, Westmead, Sydney, NSW, Australia; School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia
Ignatius Pang: Bioinformatics Group, Children's Medical Research Institute, Westmead, Sydney, NSW, Australia
Melanie Wong: The Children's Hospital at Westmead, Westmead, NSW, Australia
David Winlaw: Heart Centre, Ann and Robert H. Lurie Children's Hospital of Chicago and Feinberg School of Medicine, Northwestern University, USA
Michael Cardamone: Sydney Children's Hospital, Randwick, NSW, Australia; School of Clinical Medicine, University of New South Wales, NSW, Australia
Shekeeb Mohammad: Kids Neuroscience Centre, The Children's Hospital at Westmead, Faculty of Medicine and Health, University of Sydney, NSW, Australia; The Children's Hospital at Westmead Clinical School, Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia
Wendy Gold: School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, NSW, Australia; Molecular Neurobiology Research Laboratory, Kids Research, The Children's Hospital at Westmead & the Children's Medical Research Institute, NSW, Australia
Shrujna Patel: Kids Neuroscience Centre, The Children's Hospital at Westmead, Faculty of Medicine and Health, University of Sydney, NSW, Australia; The Children's Hospital at Westmead Clinical School, Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia
Russell C. Dale: Kids Neuroscience Centre, The Children's Hospital at Westmead, Faculty of Medicine and Health, University of Sydney, NSW, Australia; The Children's Hospital at Westmead Clinical School, Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia; The Brain and Mind Centre, The University of Sydney, Sydney, NSW, Australia; Corresponding author. Kids Neuroscience Centre, The Children's Hospital at Westmead, Faculty of Medicine and Health, University of Sydney, NSW, Australia.

Journal volume & issue: Vol. 104
p. 105156

Abstract

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Summary: 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. 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). 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. 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. 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).

Published in EBioMedicine

ISSN: 2352-3964 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Medicine: Medicine (General)
Website: http://www.journals.elsevier.com/ebiomedicine/

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