Ketogenic diet modifies ribosomal protein dysregulation in KMT2D Kabuki syndrome

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

doi:10.1016/j.ebiom.2024.105156

Ketogenic diet modifies ribosomal protein dysregulation in KMT2D Kabuki syndrome

EBioMedicine. 2024 Jun:104:105156. doi: 10.1016/j.ebiom.2024.105156. Epub 2024 May 19.

Authors

Erica Tsang¹, Velda X Han², Chloe Flutter³, Sarah Alshammery¹, Brooke A Keating⁴, Tracey Williams⁵, Brian S Gloss⁶, Mark E Graham⁷, Nader Aryamanesh⁸, Ignatius Pang⁹, Melanie Wong¹⁰, David Winlaw¹¹, Michael Cardamone¹², Shekeeb Mohammad¹, Wendy Gold¹³, Shrujna Patel¹, Russell C Dale¹⁴

Affiliations

¹ 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.
² 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.
³ The Kabuki Syndrome Foundation - Volunteer, Northbrook, IL, USA.
⁴ Kids Neuroscience Centre, The Children's Hospital at Westmead, Faculty of Medicine and Health, University of Sydney, NSW, Australia.
⁵ Kids Rehab, The Children's Hospital at Westmead, Sydney, NSW, Australia.
⁶ Westmead Research Hub, Westmead Institute for Medical Research, Westmead, NSW, Australia.
⁷ Biomedical Proteomics, Children's Medical Research Institute, The University of Sydney, Australia.
⁸ 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.
⁹ Bioinformatics Group, Children's Medical Research Institute, Westmead, Sydney, NSW, Australia.
¹⁰ The Children's Hospital at Westmead, Westmead, NSW, Australia.
¹¹ Heart Centre, Ann and Robert H. Lurie Children's Hospital of Chicago and Feinberg School of Medicine, Northwestern University, USA.
¹² Sydney Children's Hospital, Randwick, NSW, Australia; School of Clinical Medicine, University of New South Wales, NSW, Australia.
¹³ 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.
¹⁴ 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. Electronic address: [email protected].

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.

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).

Keywords: Butyrate; Epigenetic; Lysine methyltransferase; Neurodevelopment; Single-cell RNA sequencing.

MeSH terms

Abnormalities, Multiple
Child
DNA-Binding Proteins* / genetics
DNA-Binding Proteins* / metabolism
Diet, Ketogenic*
Face* / abnormalities
Female
Gene Expression Regulation
Hematologic Diseases* / diet therapy
Hematologic Diseases* / etiology
Hematologic Diseases* / genetics
Hematologic Diseases* / metabolism
Humans
Male
Mutation
Neoplasm Proteins / genetics
Neoplasm Proteins / metabolism
Proteomics* / methods
Ribosomal Proteins* / genetics
Ribosomal Proteins* / metabolism
Transcriptome
Vestibular Diseases* / diet therapy
Vestibular Diseases* / genetics
Vestibular Diseases* / metabolism

Substances

KMT2D protein, human
DNA-Binding Proteins
Ribosomal Proteins
Neoplasm Proteins

Supplementary concepts

Kabuki syndrome