Tatton-Brown-Rahman syndrome (TBRS) is a neurodevelopmental disorder of intellectual disability and neuromuscular dysfunction, caused by heterozygous mutations in the DNA methyltransferase gene, DNMT3A. We have established mouse- and cell-based models to study the molecular, cell biology and behavioural features of TBRS. In primary cultures of post-natal cortical neurons, we have performed Nanopore direct DNA methylation analysis and long read RNA sequencing to unravel the molecular mechanisms underpinning the disorder.
Further, we are using our mouse model to trial dietary interventions with supplementation of various dietary methyl donors, assessing efficacy through behavioural phenotyping. The direct methyl donor, s-adenosylmethionine, slightly improved neuromuscular phenotypes present in the mice at the tested dose. In cell models, we are trialling antisense oligonucleotides (ASOs) to increase levels of healthy DNMT3A transcripts, with a view to apply this in our mouse model.
The improvement of a patient’s ID from moderate to mild is expected to increase their chance of inclusion in mainstream schooling and workplaces. Therefore, finding interventions that improve the developmental outcomes of children with ID will substantially improve quality of life for patients and their families.