ANKS1B haploinsufficiency in a novel brain disorder

Neurodevelopmental disorders (NDDs) are highly prevalent brain diseases with enormous social and economic impacts. Failure to understand their causative molecular and cellular mechanisms is largely responsible for the paucity of available therapies. However, NDDs are highly heritable and the identification of causative single gene mutations in patients will help define underlying genetic risk factors and molecular abnormalities. We recently identified patients around the world harboring heterozygous and monogenic deletions of the ANKS1B gene. Clinical analyses reveal that affected individuals present with a spectrum of neurodevelopmental phenotypes, including autism, and speech and motor deficits. Our findings formalize a link between ANKS1B haploinsufficiency and a previously undefined syndrome we term AnkSyd. Because the mechanisms linking ANSK1B to essential cellular functions dysregulated in AnkSyd are unknown, elucidating ANKS1B function represents a key opportunity to define molecular mechanisms contributing to NDDs and normal brain function. The long-term goal of the proposed research is to define the mechanisms underlying AnkSyd and identify therapeutic targets. ANKS1B encodes for AIDA-1, a brain specific protein that is one of the most abundant proteins at neuronal synapses. Our lab found that AIDA-1 is specifically enriched at postsynaptic densities where it controls NMDA receptor (NMDAR) function by regulating the synaptic localization and function of GluN2B subunits of NMDARs. The proposed research will test the hypothesis that NMDAR dysfunction contributes to AnkSyd. Toward this purpose, we generated induced pluripotent stem cells (iPSCs) and neurons from patients and unaffected family members, as well as a transgenic mouse model that displays behavioral correlates of patient phenotypes. Overall, this proposal seeks to understand the pathophysiology of AnkSyd, a newly identified genetic syndrome presenting with autism and neurodevelopmental delays. As a monogenic disease with confirmed ANKS1B haploinsufficiency, studying AnkSyd will allow us to clearly link AIDA-1 dysfunction to cellular and behavioral outcomes. The successful completion of these experiments will reveal that NMDAR dysfunction contributes to AnkSyd pathophysiology and that ANKS1B haploinsufficiency disrupts a specific mechanism linking AIDA-1 to GluN2B. Finally, these experiments will determine the therapeutic potential of rescuing GluN2B function or other abnormal molecular pathways identified in AnkSyd models.