Our proposal is based on the hypothesis that altered metabolism is associated with 16p11.2 deletion syndrome (16pdel). We are taking a novel approach to define symptoms and treatment pathways for this severe and prevalent mental health/neurodevelopmental syndrome, affecting 1:2000 people. Deletion of one chromosomal interval, that includes 25 genes, is tightly associated with autism, intellectual disability, seizures, hyperactivity, large body size and movement disorders. All evidence points to each symptom resulting from interaction of two or more 16p11.2 genes. Strikingly, 8/25 genes in the interval encode enzymes or enzyme modulators, and our data indicates a key three-way interaction between the 16p11.2 enzymes FAM57B, a ceramide synthase; CDIPT, the only phosphatidylinositol synthase and ALDOA, a glycolytic enzyme. fam57b is a pivotal `hub' gene, as it interacts with multiple 16p11.2 homologs in the accessible whole animal zebrafish model. Encouraging preliminary data determined by metabolite profiling implicate lipid disruption as an important component to 16pdel syndrome. There are three Aims, each based on preliminary data that will be addressed in human neurons, including neurons derived from 16pdel syndrome iPS cells, with whole animal tests in the zebrafish.
The first Aim will determine changes in metabolism of human neurons and zebrafish brain, mutant for 16p11.2 enzymes.
The second aim will determine cellular and behavioral phenotypes in affected human neurons and zebrafish mutants.
The third aim will assess pharmacological modulation of mutant phenotypes. This high reward proposal will identify erroneous biochemistry that contributes to the disorder and provide an avenue for therapeutic intervention by rescuing implicated biochemical pathways.
Our goals are to devise new treatments for the prevalent and severe16p11.2 deletion syndrome, that includes autism, intellectual disability, hyperactivity, seizures and movement disorders. We have identified three key enzymes FAM57B, CDIPT and ALDOA encoded by 16p11.2 genes, whose inactivation changes the biochemistry or `metabolome' of affected cells. We will identify what is wrong with 16p11.2 deletion cells and determine whether chemicals that correct enzyme function are pioneer therapeutics for 16p11.2 deletion syndrome.
