Relevance to Autism

Two de novo loss-of-function (LoF) mutations (both nonsense variants) were reported in the CUL3 gene in unrelated ASD cases (PMIDs 22495309 and 22914163). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) in De Rubeis et al., 2014 identified CUL3 as a gene meeting high statistical significance with a FDR 0.01, meaning that this gene had a 99% chance of being a true autism gene (PMID 25363760). A third de novo LoF variant in CUL3 was identified in a Chinese ASD proband from the Autism Clinical and Genetic Resources in China (ACGC) cohort in Wang et al., 2016 (PMID 27824329). A two-stage analysis of rare de novo and inherited coding variants in 42,607 ASD cases, including 35,130 new cases from the SPARK cohort, in Zhou et al., 2022 identified CUL3 as a gene reaching exome-wide significance (P < 2.5E-06).

Molecular Function

This gene encodes a member of the cullin protein family. The encoded protein plays a critical role in the polyubiquitination and subsequent degradation of specific protein substrates as the core component and scaffold protein of an E3 ubiquitin ligase complex. Complexes including the encoded protein may also play a role in late endosome maturation.

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Model Summary

Cul3 null mice are embryonic lethal and the abnormalies start at E6.5. Cells in extraembryonic ectoderm and ectoplacental cone exhibit prolonged S phase in cell cycle, which supports that Cul3 might regulate the turnover of Cycline E. Cul3 hets have abnormal cardiovescular function, renal function, and hyperkalaemia.

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