| Autor: |
Bergamasco MI; The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia.; Department of Medical Biology and., Vanyai HK; The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia.; Department of Medical Biology and., Garnham AL; The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia.; Department of Medical Biology and., Geoghegan ND; The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia.; Department of Medical Biology and., Vogel AP; Centre for Neurosciences of Speech, University of Melbourne, Parkville, Victoria, Australia.; Redenlab Inc., Melbourne, Australia., Eccles S; The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia.; Department of Medical Biology and., Rogers KL; The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia.; Department of Medical Biology and., Smyth GK; The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia.; School of Mathematics and Statistics, University of Melbourne, Parkville, Victoria, Australia., Blewitt ME; The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia.; Department of Medical Biology and., Hannan AJ; Florey Institute of Neuroscience and Mental Health, Melbourne, Victoria, Australia.; Department of Anatomy and Physiology, University of Melbourne, Parkville, Victoria, Australia., Thomas T; The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia.; Department of Medical Biology and., Voss AK; The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia.; Department of Medical Biology and. |
| Abstrakt: |
Mutations in genes encoding chromatin modifiers are enriched among mutations causing intellectual disability. The continuing development of the brain postnatally, coupled with the inherent reversibility of chromatin modifications, may afford an opportunity for therapeutic intervention following a genetic diagnosis. Development of treatments requires an understanding of protein function and models of the disease. Here, we provide a mouse model of Say-Barber-Biesecker-Young-Simpson syndrome (SBBYSS) (OMIM 603736) and demonstrate proof-of-principle efficacy of postnatal treatment. SBBYSS results from heterozygous mutations in the KAT6B (MYST4/MORF/QFK) gene and is characterized by intellectual disability and autism-like behaviors. Using human cells carrying SBBYSS-specific KAT6B mutations and Kat6b heterozygous mice (Kat6b+/-), we showed that KAT6B deficiency caused a reduction in histone H3 lysine 9 acetylation. Kat6b+/- mice displayed learning, memory, and social deficits, mirroring SBBYSS individuals. Treatment with a histone deacetylase inhibitor, valproic acid, or an acetyl donor, acetyl-carnitine (ALCAR), elevated histone acetylation levels in the human cells with SBBYSS mutations and in brain and blood cells of Kat6b+/- mice and partially reversed gene expression changes in Kat6b+/- cortical neurons. Both compounds improved sociability in Kat6b+/- mice, and ALCAR treatment restored learning and memory. These data suggest that a subset of SBBYSS individuals may benefit from postnatal therapeutic interventions. |
