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bioRxiv · 10.64898/2026.10.03.756450

Dose dependent impact of global Cc2d1a reduction on cognitive, social, and metabolic phenotypes

Heller, A. T.·Bhattacharya, A.·Routray, P.·Rauf, S. S.·Uppalapati, V.·Suzuki, E.·Weiss, S.·Manzini, M. C.
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Abstract

Background Autism spectrum disorder (ASD) and Intellectual disability (ID) share an in-creased male prevalence, but the biological mechanisms underlying this male bias remain poorly understood. Mice deficient for CC2D1A, a protein scaffold mutated in ASD/ID, have shown multiple male-specific deficits both in ASD-like behaviors and in the regulation of neuronal intracellular signaling pathways. However, previous re-search relied on conditional knockout (cKO) models due to early postnatal lethality of global Cc2d1a KO strains. Thus, the ability to define the developmental impacts of CC2D1A LOF in mice has been limited. While generating a Cc2d1a knock-in strain with V5-HA epitope tags, we found that homozygous animals (Cc2d1aVH/VH) resulted in a hypomorph line that can be used to study developmental loss of CC2D1A. Methods We assessed gross morphology, behavior, and intracellular signaling in male and female Cc2d1aVH/VH animals, where only ~20% of CC2D1A is present. We then crossed this line with a null allele to obtain a more severe hypomorph (Cc2d1a-/VH) and explore phenotypic penetrance thresholds. In addition to the previous phenotypic characterization, we also assessed body composition, feeding, and molecular hall-marks of metabolic function in both sexes. Results We found that ~80% CC2D1A reduction in Cc2d1aVH/VH mice did not recapitu-late any of the behavioral or molecular disruptions seen in cKO models. In contrast, ~90% CC2D1A reduction in Cc2d1a-/VH mice resulted in ASD/ID-like behavioral phe-notypes in males, similar to those reported in cKO lines, with distinct intracellular sig-naling disruptions. Male and female Cc2d1a-/VH mice also showed subtle but signifi-cant adult weight deficits associated with distinct metabolic changes. Limitations These models still do not fully recapitulate the complete CC2D1A LOF found in patients. Due to the analysis of two independent strains over multiple metrics, these studies are not powered to compare statistical differences between sexes and data were analyzed in males and females independently. Conclusions We identified a strikingly narrow CC2D1A expression threshold for the emer-gence of ASD/ID-like behavioral deficits in males. In addition, we revealed a novel role for CC2D1A in adult weight gain. These mouse strains will be useful to better under-stand CC2D1A LOF phenotypes.

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Heller, A. T., Bhattacharya, A., Routray, P., Rauf, S. S., Uppalapati, V., Suzuki, E., Weiss, S., Manzini, M. C.. 2026-10-10. Dose dependent impact of global Cc2d1a reduction on cognitive, social, and metabolic phenotypes. https://doi.org/10.64898/2026.10.03.756450

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