Please use this identifier to cite or link to this item: https://ahro.austin.org.au/austinjspui/handle/1/34827
Title: A syndromic neurodevelopmental disorder caused by rare variants in PPFIA3.
Austin Authors: 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;Bacino, Carlos A;Lee, Brendan H;Chao, Hsiao-Tuan
Affiliation: Department of Pediatrics, Section of Neurology and Developmental Neuroscience, Baylor College of Medicine, Houston, TX, USA; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX, USA; Cain Pediatric Neurology Research Foundation Laboratories, Jan and Dan Duncan Neurological Research Institute, Houston, TX, USA.
Department of Pediatrics, Section of Neurology and Developmental Neuroscience, Baylor College of Medicine, Houston, TX, USA; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX, USA; Cain Pediatric Neurology Research Foundation Laboratories, Jan and Dan Duncan Neurological Research Institute, Houston, TX, USA.
Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
Cain Pediatric Neurology Research Foundation Laboratories, Jan and Dan Duncan Neurological Research Institute, Houston, TX, USA; Augustana College, Rock Island, IL, USA; Summer Undergraduate Research Training (SMART) Program, Baylor College of Medicine, Houston, TX, USA.
Department of Pediatrics, Section of Neurology and Developmental Neuroscience, Baylor College of Medicine, Houston, TX, USA; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX, USA; Graduate Program in Electrical and Computer Engineering, Rice University, Houston, TX, USA.
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
Department of Pediatrics, Section of Neurology and Developmental Neuroscience, Baylor College of Medicine, Houston, TX, USA; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX, USA; Department of Psychology, University of Houston, Houston, TX, USA.
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
Department of Pediatrics, Section of Neurology and Developmental Neuroscience, Baylor College of Medicine, Houston, TX, USA; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX, USA.
Renal Genetics Clinic, Baylor College of Medicine, Houston, TX, USA.
Rhode Island Hospital and Hasbro Children's Hospital, Providence, RI, USA.
Institute of Neurogenomics, Helmholtz Zentrum München, Munich, Germany; Institute of Human Genetics, School of Medicine, Technical University, Munich, Germany; Division of Pediatric Neurology, Developmental Neurology and Social Pediatrics, Dr. von Hauner Children's Hospital, Munich, Germany.
Institute of Human Genetics, School of Medicine, University Hospital Bonn, University of Bonn, Bonn, Germany.
Division of Pediatric Neurology, Developmental Neurology and Social Pediatrics, Dr. von Hauner Children's Hospital, Munich, Germany.
GeneDx, Gaithersburg, MD, USA.
Epilepsy NeuroGenetics Initiative (ENGIN), Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Children's Mercy Kansas City, Genomic Medicine Center, The University of Missouri-Kansas City (UMKC), School of Medicine, Kansas City, MO, USA.
Department of Pediatrics, Children's Mercy Kansas City, Kansas City, MO, USA.
Children's Mercy Kansas City, Genomic Medicine Center, The University of Missouri-Kansas City (UMKC), School of Medicine, Kansas City, MO, USA; Children's Mercy Research Institute, Kansas City, MO, USA.
Children's Mercy Hospital, Kansas City, MO, USA.
University Hospital, Dijon, France; INSERM UMR1231 GAD "Génétique des Anomalies Du Développement," FHU-TRANSLAD, University of Burgundy, Dijon, France; Functional Unit for Diagnostic Innovation in Rare Diseases, FHU-TRANSLAD, Dijon Bourgogne, France.
Functional Unit for Diagnostic Innovation in Rare Diseases, FHU-TRANSLAD, Dijon Bourgogne, France; Department of Genetics and Reference Center for Development Disorders and Intellectual Disabilities, FHU-TRANSLAD and GIMI Institute, Dijon Bourgogne University Hospital, Dijon, France.
University Hospital, Dijon, France; INSERM UMR1231 GAD "Génétique des Anomalies Du Développement," FHU-TRANSLAD, University of Burgundy, Dijon, France; Functional Unit for Diagnostic Innovation in Rare Diseases, FHU-TRANSLAD, Dijon Bourgogne, France.
Department of Pediatrics, Section of Neurology and Developmental Neuroscience, Baylor College of Medicine, Houston, TX, USA; Department of Neurology, Boston Children's Hospital, Boston, MA, USA.
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Department of Neurology, Boston Children's Hospital, Boston, MA, USA.
Institute for Human Genetics and Genomic Medicine, Medical Faculty, RWTH, Aachen University, Aachen, Germany.
Medical Treatment Center for Adults with Intellectual Disabilities and/or Severe Multiple Disabilities (MZEB), RWTH Aachen University Hospital, Aachen, Germany.
Department of Pediatrics, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran; Neuroscience Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
Department of Medical Genetics, Next Generation Genetic Polyclinic, Mashhad, Iran; Molecular and Clinical Sciences Institute, St. George's, University of London, Cranmer Terrace, London, UK.
Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, UK.
University of Arkansas for Medical Sciences; Little Rock, AR, USA.
LNR Genomics Medicine, University Hospitals of Leicester, Leicester, UK.
London Health Sciences Centre, and Division of Medical Genetics, Department of Pediatrics, Western University, London, ON, Canada.
Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, ON, Canada.
Institute of Human Genetics, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
Epilepsy Research Centre
Department of Pediatrics, University of Melbourne, Royal Children's Hospital, Florey and Murdoch Children's Research Institutes, VIC, Melbourne, Australia.
Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
Center for Pediatric Neurological Disease Research, St. Jude Children's Research Hospital, Memphis, TN, USA.
Department of Pediatrics, Section of Neurology and Developmental Neuroscience, Baylor College of Medicine, Houston, TX, USA; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX, USA; Cain Pediatric Neurology Research Foundation Laboratories, Jan and Dan Duncan Neurological Research Institute, Houston, TX, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA; Texas Children's Hospital, Houston, TX, USA; Department of Neuroscience, Baylor College of Medicine, Houston, TX, USA; McNair Medical Institute, The Robert and Janice McNair Foundation, Houston, TX, USA.
Issue Date: 4-Jan-2024
Publication information: American Journal of Human Genetics 2024-01-04; 111(1)
Abstract: 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.
URI: https://ahro.austin.org.au/austinjspui/handle/1/34827
DOI: 10.1016/j.ajhg.2023.12.004
ORCID: 
Journal: American Journal of Human Genetics
Start page: 96
End page: 118
PubMed URL: 38181735
ISSN: 1537-6605
Type: Journal Article
Subjects: Mendelian phenotypes
active zone protein
fruit flies
neurodevelopmental disorder
synaptic protein
Neurodevelopmental Disorders/genetics
Intellectual Disability/genetics
Drosophila Proteins/genetics
Appears in Collections:Journal articles

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