TY - JOUR
T1 - A syndromic neurodevelopmental disorder caused by rare variants in PPFIA3
AU - Undiagnosed Diseases Network
AU - Paul, Maimuna S.
AU - Michener, Sydney L.
AU - Pan, Hongling
AU - Chan, Hiuling
AU - Pfliger, Jessica M.
AU - Rosenfeld, Jill A.
AU - Lerma, Vanesa C.
AU - Tran, Alyssa
AU - Longley, Megan A.
AU - Lewis, Richard A.
AU - Weisz-Hubshman, Monika
AU - Bekheirnia, Mir Reza
AU - Bekheirnia, Nasim
AU - Massingham, Lauren
AU - Zech, Michael
AU - Wagner, Matias
AU - Engels, Hartmut
AU - Cremer, Kirsten
AU - Mangold, Elisabeth
AU - Peters, Sophia
AU - Trautmann, Jessica
AU - Mester, Jessica L.
AU - Guillen Sacoto, Maria J.
AU - Person, Richard
AU - McDonnell, Pamela P.
AU - Cohen, Stacey R.
AU - Lusk, Laina
AU - Cohen, Ana S.A.
AU - Le Pichon, Jean Baptiste
AU - Pastinen, Tomi
AU - Zhou, Dihong
AU - Engleman, Kendra
AU - Racine, Caroline
AU - Faivre, Laurence
AU - Moutton, Sébastien
AU - Denommé-Pichon, Anne Sophie
AU - Koh, Hyun Yong
AU - Poduri, Annapurna
AU - Bolton, Jeffrey
AU - Knopp, Cordula
AU - Julia Suh, Dong Sun
AU - Maier, Andrea
AU - Toosi, Mehran Beiraghi
AU - Karimiani, Ehsan Ghayoor
AU - Maroofian, Reza
AU - Dasari, Surendra
AU - Lanpher, Brendan C.
AU - Lanza, Ian R.
AU - Morava, Eva
AU - Oglesbee, Devin
N1 - Publisher Copyright:
© 2023 American Society of Human Genetics
PY - 2024/1/4
Y1 - 2024/1/4
N2 - 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.
AB - 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.
KW - Mendelian phenotypes
KW - active zone protein
KW - fruit flies
KW - neurodevelopmental disorder
KW - synaptic protein
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UR - http://www.scopus.com/inward/citedby.url?scp=85181848634&partnerID=8YFLogxK
U2 - 10.1016/j.ajhg.2023.12.004
DO - 10.1016/j.ajhg.2023.12.004
M3 - Article
C2 - 38181735
AN - SCOPUS:85181848634
SN - 0002-9297
VL - 111
SP - 96
EP - 118
JO - American journal of human genetics
JF - American journal of human genetics
IS - 1
ER -