Relevance to Autism

De novo variants in the PC gene have been identified in ASD probands, including a de novo missense variant (p.Pro1042Arg) in a proband from the Simons Simplex Collection (Iossifov et al., 2014; Sanders et al., 2015; Yuen et al., 2016; Yuen et al., 2017; Turner et al., 2017). Targeted sequencing of 136 microcephaly or macrocephaly-related genes and 158 possible ASD risk genes in 536 Chinese ASD probands from the Autism Clinical and Genetic Resources in China (ACGC) cohort in Li et al., 2017 identified additional missense variants in the PC gene, and a inherited loss-of-function variant in this gene was observed in an ASD proband from a multiplex family from the iHART cohort (Ruzzo et al., 2019). Functional assessment of the ASD-associated p.Pro1042Arg missense variant in Drosophila using an overexpression-based strategy in Macrogliese et al., 2022 demonstrated that flies overexpressing PC-p.Pro1042Arg exhibited increased lethality when compared with reference protein, indicating a gain-of-function effect.

Molecular Function

This gene encodes pyruvate carboxylase, which requires biotin and ATP to catalyse the carboxylation of pyruvate to oxaloacetate. The active enzyme is a homotetramer arranged in a tetrahedron which is located exclusively in the mitochondrial matrix. Pyruvate carboxylase is involved in gluconeogenesis, lipogenesis, insulin secretion and synthesis of the neurotransmitter glutamate. Biallelic variants in this gene are associated with pyruvate carboxylase deficiency (OMIM 266150); neurological phenotypes associated with this disease include developmental delay, intellectual disability, and seizures.

External Links

References