Investigating Sex-Specific CC2D1A Function to Understand Sex Bias in Neurodevelopemental Disorders

Autism spectrum disorder (ASD) and intellectual disability (ID) are neurodevelopmental conditions marked by striking genetic and clinical complexity. Both disorders show a well-documented male diagnostic bias (4:1 for ASD and 2:1 for ID), yet the bio-logical mechanisms underlying this sex disparity remain poorly understood. Previous research has identified CC2D1A loss of function (LOF) as a cause of fully penetrant ID, and highly penetrant ASD, making it a critical model for studying these conditions. CC2D1A functions as a membrane-proximal signaling scaffold, facilitating the assembly of intracellular complexes and the propagation of downstream signaling cascades. This dissertation presents the most comprehensive characterization of the CC2D1A interactome to date. I demonstrate that CC2D1A co-localizes with Charged Multivesicular Body Protein 4B (CHMP4B) across multiple subcellular compartments to coordinate membrane remodeling and cell signaling. I also identify a previously unrecognized, predominantly postsynaptic role for CC2D1A, with interacting partners involved in dendritic spine formation and stabilization, offering a mechanistic framework for how CC2D1A LOF may produce its neurodevelopmental phenotypes. Studying the behavioral consequences of CC2D1A loss in mice has been hindered by early postnatal lethality in global knockouts, while existing conditional knockout (cKO) lines reveal male specific deficits they incompletely recapitulate the developmental nature of patient mutations. In this work I characterize two novel global and developmental Cc2d1a hypomorph lines, one with 80% and the other with 90% CC2D1A reduction, both of which bypass early lethality. Comparison of these lines re-veal a narrow expression threshold governing the penetrance of behavioral deficits. The 90% reduction model produces male-specific ASD/ID-like behavioral phenotypes consistent with those seen in cKO models but driven by a distinct intracellular signal-ing disruption. Finally, this work reveals a novel role for CC2D1A as a sex specific regulator of growth and weight. Collectively, this work advances our understanding of the molecular mechanisms underlying CC2D1A LOF and provides new insight into the biological basis of male-biased prevalence in ASD and ID.