A syndromic neurodevelopmental disorder caused by rare variants in PPFIA3.
СтатьяПоддержка исследования: вне правительства СШАПоддержка NIH: внешняя программаНазвание и аннотация: Перевод в очереди
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Paul Maimuna S, Michener Sydney L, Pan Hongling, Chan Hiuling, Pfliger Jessica M, Rosenfeld Jill A, Lerma Vanesa C, Tran Alyssa, Longley Megan A, Lewis Richard A, Weisz-Hubshman Monika, Bekheirnia Mir Reza, Bekheirnia Nasim, Massingham Lauren, Zech Michael, Wagner Matias, Engels Hartmut, Cremer Kirsten, Mangold Elisabeth, Peters Sophia, Trautmann Jessica, Mester Jessica L, Guillen Sacoto Maria J, Person Richard, McDonnell Pamela P, Cohen Stacey R, Lusk Laina, Cohen Ana S A, Le Pichon Jean-Baptiste, Pastinen Tomi, Zhou Dihong, Engleman Kendra, Racine Caroline, Faivre Laurence, Moutton Sébastien, Denommé-Pichon Anne-Sophie, Koh Hyun Yong, Poduri Annapurna, Bolton Jeffrey, Knopp Cordula, Julia Suh Dong Sun, Maier Andrea, Toosi Mehran Beiraghi, Karimiani Ehsan Ghayoor, Maroofian Reza, Schaefer Gerald Bradley, Ramakumaran Vijayalakshmi, Vasudevan Pradeep, Prasad Chitra, Osmond Matthew, Schuhmann Sarah, Vasileiou Georgia, Russ-Hall Sophie, Scheffer Ingrid E, Carvill Gemma L, Mefford Heather, Undiagnosed Diseases Network, Bacino Carlos A, Lee Brendan H, Chao Hsiao-Tuan
Аннотация
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.