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Paul, M.S.* ; Michener, S.L.* ; Pan, H.* ; Chan, H.* ; Pfliger, J.M.* ; Rosenfeld, J.A.* ; Lerma, V.C.* ; Tran, A.* ; Longley, M.A.* ; Lewis, R.A.* ; Weisz-Hubshman, M.* ; Bekheirnia, M.R.* ; Bekheirnia, N.* ; Massingham, L.* ; Zech, M. ; Wagner, M. ; Engels, H.* ; Cremer, K.* ; Mangold, E.* ; Peters, S.* ; Trautmann, J.* ; Mester, J.L.* ; Guillen Sacoto, M.J.* ; Person, R.* ; McDonnell, P.P.* ; Cohen, S.R.* ; Lusk, L.* ; Cohen, A.S.A.* ; Le Pichon, J.B.* ; Pastinen, T.* ; Zhou, D.* ; Engleman, K.* ; Racine, C.* ; Faivre, L.* ; Moutton, S.* ; Denommé-Pichon, A.S.* ; Koh, H.Y.* ; Poduri, A.* ; Bolton, J.L.* ; Knopp, C.* ; Julia Suh, D.S.* ; Maier, A.* ; Toosi, M.B.* ; Karimiani, E.G.* ; Maroofian, R.* ; Schaefer, G.B.* ; Ramakumaran, V.S.* ; Vasudevan, P.* ; Prasad, C.* ; Osmond, M.* ; Schuhmann, S.* ; Vasileiou, G.* ; Russ-Hall, S.* ; Scheffer, I.E.* ; Carvill, G.L.* ; Mefford, H.C.* ; Bacino, C.A.* ; Lee, B.H.* ; Chao, H.T.*

A syndromic neurodevelopmental disorder caused by rare variants in PPFIA3.

Am. J. Hum. Genet. 111, 96-118 (2024)
Postprint DOI PMC
Open Access Green
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.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Mendelian Phenotypes ; Active Zone Protein ; Fruit Flies ; Neurodevelopmental Disorder ; Synaptic Protein; Protein-tyrosine-phosphatase; Liprin-alpha Family; Active Zone; Neurotransmitter Release; Sam Domain; Lar; Expression; Framework; Regions; Binding
Sprache englisch
Veröffentlichungsjahr 2024
HGF-Berichtsjahr 2024
ISSN (print) / ISBN 0002-9297
e-ISSN 1537-6605
Zeitschrift American Journal of Human Genetics, The
Quellenangaben Band: 111, Heft: 1, Seiten: 96-118 Artikelnummer: , Supplement: ,
Verlag Elsevier
Verlagsort New York, NY
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Neurogenomics (ING)
POF Topic(s) 30205 - Bioengineering and Digital Health
Forschungsfeld(er) Genetics and Epidemiology
PSP-Element(e) G-503200-001
Förderungen NIH Common Fund, through the Office of Strategic Coordination/Office of the NIH Director
Elkins Foundation
Mark A. Wallace Endowment Award
National Ataxia Foundation
Burroughs Wellcome Fund
Gordan and Mary Cain Foundation
Texas Children's Hospital
Jan and Dan Duncan Neurological Research Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development of the National Institutes of Health
McNair Medical Institute at The Robert and Janice McNair Foundation
DOI 10.1016/j.ajhg.2023.12.004
WOS ID 001154201800001
Scopus ID 85181848634
PubMed ID 38181735
Erfassungsdatum 2024-03-28
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