A syndromic neurodevelopmental disorder caused by rare variants in PPFIA3

Paul MS, Michener SL, Pan H, Chan H, Pfliger JM, Rosenfeld JA, Lerma VC, Tran A, Longley MA, Lewis RA, Weisz-Hubshman M, Bekheirnia MR, Bekheirnia N, Massingham L, Zech M, Wagner M, Engels H, Cremer K, Mangold E, Peters S, Trautmann J, Mester JL, Guillen Sacoto MJ, Person R, McDonnell PP, Cohen SR, Lusk L, Cohen AS, Le Pichon JB, Pastinen T, Zhou D, Engleman K, Racine C, Faivre L, Moutton S, Denommé-Pichon AS, Koh HY, Poduri A, Bolton J, Knopp C, Julia Suh DS, Maier A, Toosi MB, Karimiani EG, Maroofian R, Schaefer GB, Ramakumaran V, Vasudevan P, Prasad C, Osmond M, Schuhmann S, Vasileiou G, Russ-Hall S, Scheffer IE, Carvill GL, Mefford H, Bacino CA, Lee BH, Chao HT (2024)

Publication Type: Journal article

Publication year: 2024


Book Volume: 111

Pages Range: 96-118

Journal Issue: 1

DOI: 10.1016/j.ajhg.2023.12.004


PPFIA3 encodes the protein-tyrosine phosphatase, receptor-type, F-polypeptide-interacting-protein-alpha-3 (PPFIA3), which is a member of the LAR-protein-tyrosine phosphatase-interacting-protein (liprin) family involved in synapse formation and function, synaptic vesicle transport, and presynaptic active zone assembly. The protein structure and function are evolutionarily well conserved, but human diseases related to PPFIA3 dysfunction are not yet reported in OMIM. Here, we report 20 individuals with rare PPFIA3 variants (19 heterozygous and 1 compound heterozygous) presenting with developmental delay, intellectual disability, hypotonia, dysmorphisms, microcephaly or macrocephaly, autistic features, and epilepsy with reduced penetrance. Seventeen unique PPFIA3 variants were detected in 18 families. To determine the pathogenicity of PPFIA3 variants in vivo, we generated transgenic fruit flies producing either human wild-type (WT) PPFIA3 or five missense variants using GAL4-UAS targeted gene expression systems. In the fly overexpression assays, we found that the PPFIA3 variants in the region encoding the N-terminal coiled-coil domain exhibited stronger phenotypes compared to those affecting the C-terminal region. In the loss-of-function fly assay, we show that the homozygous loss of fly Liprin-α leads to embryonic lethality. This lethality is partially rescued by the expression of human PPFIA3 WT, suggesting human PPFIA3 function is partially conserved in the fly. However, two of the tested variants failed to rescue the lethality at the larval stage and one variant failed to rescue lethality at the adult stage. Altogether, the human and fruit fly data reveal that the rare PPFIA3 variants are dominant-negative loss-of-function alleles that perturb multiple developmental processes and synapse formation.

Authors with CRIS profile

Involved external institutions

Baylor College of Medicine US United States (USA) (US) Centre hospitalier universitaire (CHU) de Dijon Bourgogne FR France (FR) Children's Hospital of Philadelphia US United States (USA) (US) Augustana College US United States (USA) (US) University of Missouri–Kansas City (UMKC) US United States (USA) (US) Children's Mercy Hospital US United States (USA) (US) Boston Children's Hospital US United States (USA) (US) Hasbro Children's Hospital US United States (USA) (US) Helmholtz Zentrum München - Deutsches Forschungszentrum für Gesundheit und Umwelt (HMGU) / Helmholtz Munich DE Germany (DE) Universitätsklinikum Bonn DE Germany (DE) Klinikum der Universität München DE Germany (DE) GeneDX US United States (USA) (US) Texas Children's Hospital US United States (USA) (US) Rheinisch-Westfälische Technische Hochschule (RWTH) Aachen DE Germany (DE) Universitätsklinikum Aachen (UKA) DE Germany (DE) Mashhad University of Medical Sciences (MUMS) IR Iran, Islamic Republic of (IR) St George's, University of London (SGUL) / St George's Hospital Medical School GB United Kingdom (GB) University College London (UCL) GB United Kingdom (GB) University of Arkansas for Medical Sciences (UAMS) US United States (USA) (US) University Hospitals of Leicester NHS Trust GB United Kingdom (GB) Western University CA Canada (CA) The University of Melbourne AU Australia (AU) Children's Hospital of Eastern Ontario (CHEO) / Centre hospitalier pour enfants de l'est de l'Ontario CA Canada (CA) Northwestern University US United States (USA) (US) St. Jude Children’s Research Hospital US United States (USA) (US)

How to cite


Paul, M.S., Michener, S.L., Pan, H., Chan, H., Pfliger, J.M., Rosenfeld, J.A.,... Chao, H.T. (2024). A syndromic neurodevelopmental disorder caused by rare variants in PPFIA3. American Journal of Human Genetics, 111(1), 96-118. https://doi.org/10.1016/j.ajhg.2023.12.004


Paul, Maimuna S., et al. "A syndromic neurodevelopmental disorder caused by rare variants in PPFIA3." American Journal of Human Genetics 111.1 (2024): 96-118.

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