Relevance to Autism

CAD was identified as an ASD candidate gene in Wilfert et al., 2021 based on the discovery of private likely gene-disruptive (LGD) variants in this highly constrained (pLI 0.99) gene that were exclusively transmitted to four ASD probands in four independent families. A de novo missense variant in this gene had previously been identified in an ASD proband from the Simons Simplex Collection (Iossifov et al., 2014). Biallelic variants in CAD have previously been shown to be associated with developmental and epileptic encephalopathy-50 (DEE50; OMIM 616457), an autosomal recessive progressive neurodegenerative neurometabolic disorder characterized by delayed psychomotor development, early-onset refractory seizures, severe developmental regression, and normocytic anemia (Ng et al., 2015; Koch et al., 2017).

Molecular Function

The de novo synthesis of pyrimidine nucleotides is required for mammalian cells to proliferate. This gene encodes a trifunctional protein which is associated with the enzymatic activities of the first 3 enzymes in the 6-step pathway of pyrimidine biosynthesis: carbamoylphosphate synthetase (CPS II), aspartate transcarbamoylase, and dihydroorotase. This protein is regulated by the mitogen-activated protein kinase (MAPK) cascade, which indicates a direct link between activation of the MAPK cascade and de novo biosynthesis of pyrimidine nucleotides.

External Links

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