Ppfia3, encoding Protein-Tyrosine Phosphatase, Receptor-Type, F Polypeptide-Interacting Protein Alpha-3, is a member of the LAR-protein-tyrosine phosphatase-interacting-protein (liprin) family. It is involved in synapse formation and function, synaptic vesicle transport, and presynaptic active zone assembly. Its protein structure and function are evolutionarily conserved [1,2]. Fruit fly models are valuable for in vivo functional studies of Ppfia3.

In a study, 20 individuals with rare Ppfia3 variants (19 heterozygous and 1 compound heterozygous) presented with developmental delay, intellectual disability, hypotonia, dysmorphisms, microcephaly or macrocephaly, autistic features, and epilepsy with reduced penetrance. Transgenic fruit flies expressing human wild-type (WT) PPFIA3 or missense variants were generated. In fly overexpression assays, variants in the N-terminal coiled-coil domain of PPFIA3 showed stronger phenotypes. In loss-of-function fly assays, homozygous loss of fly Liprin-α led to embryonic lethality, which was partially rescued by human PPFIA3 WT, but some variants failed to rescue lethality at different stages. This indicates that rare PPFIA3 variants are dominant-negative loss-of-function alleles that disrupt multiple developmental processes and synapse formation [1]. Another study on 14 individuals with rare mono-allelic PPFIA3 variants had similar phenotypic findings, and fly assays also showed variable penetrance of pupal lethality, eclosion defects, anatomical leg defects, seizure-like behaviors, motor defects, and bouton loss at the 3rd instar larval neuromuscular junction (NMJ) for PPFIA3 variants [2].

In conclusion, Ppfia3 is essential for synapse-related functions. Model-based research, especially using fruit fly models, has revealed that loss-of-function variants of Ppfia3 can lead to a syndromic neurodevelopmental disorder characterized by developmental delay, intellectual disability, and other neurological features, contributing to our understanding of the role of Ppfia3 in neurodevelopmental diseases [1,2].

References:

1. Paul, Maimuna S, Michener, Sydney L, Pan, Hongling, Lee, Brendan H, Chao, Hsiao-Tuan. . A syndromic neurodevelopmental disorder caused by rare variants in PPFIA3. In American journal of human genetics, 111, 96-118. doi:10.1016/j.ajhg.2023.12.004. https://pubmed.ncbi.nlm.nih.gov/38181735/

2. Paul, Maimuna S, Michener, Sydney L, Pan, Hongling, Lee, Brendan H, Chao, Hsiao-Tuan. 2023. Rare variants in PPFIA3 cause delayed development, intellectual disability, autism, and epilepsy. In medRxiv : the preprint server for health sciences, , . doi:10.1101/2023.03.27.23287689. https://pubmed.ncbi.nlm.nih.gov/37034625/