Introduction:
Although many autism-related genes have been identified, the underlying etiological mechanisms remain unclear. This study investigates the hypothesis that autism-associated proteins, despite their diverse functional annotations, converge in localization, expression, and function in cilia, organelles essential for neurogenesis, brain patterning, and neuronal activity. The role of cilia in autism and comorbid conditions such as congenital heart disease and epilepsy has not been systematically explored before.
Methods:
Using proteomic analyses and biological systems, high-confidence proteins associated with autism were investigated, evaluating their relationship with proteomes derived from cilia and associated structures, such as centrioles. Experimental methods included in vitro modeling in primary neurons and in vivo in Xenopus tropicalis to characterize the localization and functionality of target proteins in cilia. CRISPR mutagenesis assays and the use of human variants were used to validate ciliary functions, with evaluation of clinical biomarkers such as nasal nitric oxide (nNO).
Results:
Highly confident autism-associated genes were found to be enriched in cilia-related proteomes, especially in regions proximal to the basal body. Among 30 proteins statistically associated with autism, 12 were localized to both primary and motile cilia. Missense variants of SYNGAP1, a gene related to neuronal communication, affected its ciliary localization and biomarkers of ciliary function. Furthermore, chromatin regulators such as CHD8 and POGZ, previously not associated with cilia, were shown to be critical for ciliogenesis.
Discussion:
This study redefines the biological relevance of autism-related genes by linking ciliary anomalies with comorbid conditions. The findings suggest that traditional functional categorizations, such as gene regulation and neuronal communication, underestimate the roles of these genes. Integrating ciliary and synaptic functions offers new avenues for biomarkers and therapies for refractory epilepsies and other conditions.
Conclusion:
This work provides robust evidence that autism-associated genes play essential roles in cilia, expanding our understanding of the biology of autism and comorbid conditions. Future research should further explore the contributions of cilia to the etiology of autism and its therapeutic potential.
Reference :
KOSTYANOVSKAYA, Elina; LASSER, Micaela C.; WANG, Belinda; SCHMIDT, James; BADER, Ethel; BUTEO, Chad; ARBELAEZ, Juan; SINDLEDECKER, Aria Rani; MCCLUSKEY, Kate E.; CASTILLO, Octavio; WANG, Sheng; DEA, Jeanselle; HELDE, Kathryn A.; GRAGLIA, J. Michael; BRIMBLE, Elise; KASTNER, David B.; EHRLICH, Aliza T.; STATE, Matthew W.; WILLSEY, A. Jeremy; WILLSEY, Helen Rankin. Convergence of autism proteins at the cilium. bioRxiv. 2024. Available at: https://doi.org/10.1101/2024.12.05.626924. Accessed on: 27 Jan. 2025.
