Paul et al., 2024 reported 20 individuals with rare PPFIA3 variants (19 heterozygous and 1 compound heterozygous) presenting with a neurodevelopmental syndrome characterized by developmental delay, intellectual disability, hypotonia, dysmorphic features, microcephaly or macrocephaly, and epilepsy; a co-morbid diagnosis of autism spectrum disorder was reported in four of these individuals, while an additional five individuals presented with autistic features without a formal diagnosis of ASD. Additional de novo variants in the PPFIA3 gene, including three de novo missense variants and a de novo splice-region variant, have been identified in ASD probands (Yuen et al., 2017; Satterstrom et al., 2020; Zhou et al., 2022; Trost et al., 2022). Wilfert et al., 2021 identified PPFIA3 as an ASD candidate gene based on the transmission of private likely gene-disruptive (LGD) variants exclusively to probands in two or more unrelated families.
Molecular Function
The protein encoded by this gene is a member of the LAR protein-tyrosine phosphatase-interacting protein (liprin) family. Liprins interact with members of LAR family of transmembrane protein tyrosine phosphatases, which are known to be important for axon guidance and mammary gland development. Liprin family protein has been shown to localize phosphatase LAR to cell focal adhesions and may be involved in the molecular organization of presynaptic active zones. Wong et al., 2018 observed that Ppfia3 knockout mice generated by CRISPR/Cas9 gene editing exhibited reduced synaptic vesicle tethering and docking in hippocampal neurons, impaired synaptic vesicle exocytosis, and mild alterations in active zone structure.
