RESUMEN
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).
Asunto(s)
Proteínas de Unión al ADN , Dieta Cetogénica , Cara , Enfermedades Hematológicas , Proteómica , Proteínas Ribosómicas , Enfermedades Vestibulares , Enfermedades Vestibulares/genética , Enfermedades Vestibulares/metabolismo , Enfermedades Vestibulares/dietoterapia , Humanos , Cara/anomalías , Masculino , Enfermedades Hematológicas/metabolismo , Enfermedades Hematológicas/genética , Enfermedades Hematológicas/etiología , Enfermedades Hematológicas/dietoterapia , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Proteínas Ribosómicas/genética , Proteínas Ribosómicas/metabolismo , Niño , Proteómica/métodos , Femenino , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Regulación de la Expresión Génica , Mutación , Transcriptoma , Anomalías MúltiplesRESUMEN
Kabuki syndrome is a Mendelian intellectual disability syndrome caused by mutations in either of two genes (KMT2D and KDM6A) involved in chromatin accessibility. We previously showed that an agent that promotes chromatin opening, the histone deacetylase inhibitor (HDACi) AR-42, ameliorates the deficiency of adult neurogenesis in the granule cell layer of the dentate gyrus and rescues hippocampal memory defects in a mouse model of Kabuki syndrome (Kmt2d+/ßGeo). Unlike a drug, a dietary intervention could be quickly transitioned to the clinic. Therefore, we have explored whether treatment with a ketogenic diet could lead to a similar rescue through increased amounts of beta-hydroxybutyrate, an endogenous HDACi. Here, we report that a ketogenic diet in Kmt2d+/ßGeo mice modulates H3ac and H3K4me3 in the granule cell layer, with concomitant rescue of both the neurogenesis defect and hippocampal memory abnormalities seen in Kmt2d+/ßGeo mice; similar effects on neurogenesis were observed on exogenous administration of beta-hydroxybutyrate. These data suggest that dietary modulation of epigenetic modifications through elevation of beta-hydroxybutyrate may provide a feasible strategy to treat the intellectual disability seen in Kabuki syndrome and related disorders.
Asunto(s)
Anomalías Múltiples/dietoterapia , Dieta Cetogénica/métodos , Cara/anomalías , Enfermedades Hematológicas/dietoterapia , Hipocampo/metabolismo , Histonas/biosíntesis , Discapacidad Intelectual/dietoterapia , Neurogénesis/fisiología , Enfermedades Vestibulares/dietoterapia , Ácido 3-Hidroxibutírico/metabolismo , Anomalías Múltiples/genética , Animales , Modelos Animales de Enfermedad , Enfermedades Hematológicas/genética , Hipocampo/citología , Histona Demetilasas/genética , N-Metiltransferasa de Histona-Lisina/genética , Discapacidad Intelectual/genética , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Proteína de la Leucemia Mieloide-Linfoide/genética , Neurogénesis/genética , Enfermedades Vestibulares/genéticaRESUMEN
A prevalência dos diversos tipos de hiperinsulinismo como causa de distúrbios otoneurológicos é realçada. Säo apresentados detalhes da história clínica e do exame otoneurólogico, importantes para a suspeita diagnóstica. A curva insulinêmica de cinco horas, conjuntamente com a curva glicêmica é considerada fundamental para a confirmaçäo etiológica. Resultados extremamente favoráveis com relaçäo à remissäo parcial ou total de tonturas, zumbido e hipoacusia e outros sintomas correlacionados foram obtidos com tratamento por meio de dieta nutricional e modificaçäo de alguns hábitos, sem uso de medicamentos. O exame otoneurológico foi considerado útil no acompanhamento da evoluçäo das labirintopatias por hiperinsulinismo com o tratamento dietético instituído por toda a vida dos pacientes.
