Pantothenate and L-Carnitine Supplementation Improves Pathological Alterations in Cellular Models of KAT6A Syndrome

Abstract

Mutations in several genes involved in the epigenetic regulation of gene expression have been considered risk alterations to different intellectual disability (ID) syndromes associated with features of autism spectrum disorder (ASD). Among them are the pathogenic variants of the lysine-acetyltransferase 6A (KAT6A) gene, which causes KAT6A syndrome. The KAT6A enzyme participates in a wide range of critical cellular functions, such as chromatin remodeling, gene expression, protein synthesis, cell metabolism, and replication. In this manuscript, we examined the pathophysiological alterations in fibroblasts derived from three patients harboring KAT6A mutations. We addressed survival in a stress medium, histone acetylation, protein expression patterns, and transcriptome analysis, as well as cell bioenergetics. In addition, we evaluated the therapeutic effectiveness of epigenetic modulators and mitochondrial boosting agents, such as pantothenate and L-carnitine, in correcting the mutant phenotype. Pantothenate and L-carnitine treatment increased histone acetylation and partially corrected protein and transcriptomic expression patterns in mutant KAT6A cells. Furthermore, the cell bioenergetics of mutant cells was significantly improved. Our results suggest that pantothenate and L-carnitine can significantly improve the mutant phenotype in cellular models of KAT6A syndrome.

Relation Between Reactive Oxygen Species Production and Transient Receptor Potential Vanilloid1 Expression in Human Skin During Aging

“…52 Skin sections were incubated for 45 minutes at 37°C and for 1 hour at room temperature with the following primary antibodies: rabbit polyclonal anti-TRPV1 (working concentration 1 µg/ml; diluted 1:350; Abcam, Cambrige, UK), 53 rabbit polyclonal anti-MMP9 (working concentration 1 µg/ml; diluted 1:400; Abbiotec, San Diego, CA, USA), rabbit polyclonal anticyclooxygenase-2 (COX-2) (working concentration 0.5 µg/ml; diluted 1:400; Cayman Chemical, Ann Arbor, MI, USA), 54 and mouse monoclonal antisuperoxide dismutase-1(SOD-1) (working concentration 2 µg/ml; diluted 1:100; Santa Cruz Biotechnology, Dallas, TX, USA). 55–57 Then, the sections were incubated for 1 hour with specific biotinylated secondary antibodies (Vector Laboratories, Newark, CA, USA) and subsequently conjugated with avidin-biotin peroxidase complex (Vector Laboratories, Burlingame, CA, USA). The reaction products were visualized using 0.33% hydrogen peroxide and 0.05% 3,3ʹ-diaminobenzidine tetrahydrochloride, as chro-mogen (Sigma, St. Louis, MO, USA).…”

Intellectual disability: A potentially treatable condition

“…Modification of histones can be influenced by increasing the substrates and this may be a potential mechanism of treatment in Arboleda‐Tham syndrome 31 . Experiments in fibroblasts have demonstrated that acetylation is improved by treatment using L‐carnitine and pantothenate (vitamin B5), two readily available dietary supplements 35 . The impact of this treatment is not yet known on neural models of the disease, which may be more relevant to human disease affecting the brain, whilst another unknown is what therapeutic range that would be optimal for treatment.…”