Your browser doesn't support javascript.
loading
A syndromic neurodevelopmental disorder caused by rare variants in PPFIA3.
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.
Afiliación
  • Paul MS; 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
  • Michener SL; 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
  • Pan H; 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.
  • Chan H; 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.
  • Pfliger JM; 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, Hous
  • Rosenfeld JA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
  • Lerma VC; 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.
  • Tran A; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
  • Longley MA; 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.
  • Lewis RA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA; Department of Ophthalmology, Baylor College of Medicine, Houston, TX, USA.
  • Weisz-Hubshman M; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
  • Bekheirnia MR; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA; Renal Genetics Clinic, Baylor College of Medicine, Houston, TX, USA.
  • Bekheirnia N; Renal Genetics Clinic, Baylor College of Medicine, Houston, TX, USA.
  • Massingham L; Rhode Island Hospital and Hasbro Children's Hospital, Providence, RI, USA.
  • Zech M; Institute of Neurogenomics, Helmholtz Zentrum München, Munich, Germany; Institute of Human Genetics, School of Medicine, Technical University, Munich, Germany; Institute for Advanced Study, Technical University of Munich, Garching, Germany.
  • Wagner M; 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.
  • Engels H; Institute of Human Genetics, School of Medicine, University Hospital Bonn, University of Bonn, Bonn, Germany.
  • Cremer K; Division of Pediatric Neurology, Developmental Neurology and Social Pediatrics, Dr. von Hauner Children's Hospital, Munich, Germany.
  • Mangold E; Division of Pediatric Neurology, Developmental Neurology and Social Pediatrics, Dr. von Hauner Children's Hospital, Munich, Germany.
  • Peters S; Division of Pediatric Neurology, Developmental Neurology and Social Pediatrics, Dr. von Hauner Children's Hospital, Munich, Germany.
  • Trautmann J; Division of Pediatric Neurology, Developmental Neurology and Social Pediatrics, Dr. von Hauner Children's Hospital, Munich, Germany.
  • Mester JL; GeneDx, Gaithersburg, MD, USA.
  • Guillen Sacoto MJ; GeneDx, Gaithersburg, MD, USA.
  • Person R; GeneDx, Gaithersburg, MD, USA.
  • McDonnell PP; Epilepsy NeuroGenetics Initiative (ENGIN), Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA, USA; Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • Cohen SR; Epilepsy NeuroGenetics Initiative (ENGIN), Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
  • Lusk L; Epilepsy NeuroGenetics Initiative (ENGIN), Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
  • Cohen ASA; Children's Mercy Kansas City, Genomic Medicine Center, The University of Missouri-Kansas City (UMKC), School of Medicine, Kansas City, MO, USA.
  • Le Pichon JB; Department of Pediatrics, Children's Mercy Kansas City, Kansas City, MO, USA.
  • Pastinen T; 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.
  • Zhou D; Children's Mercy Hospital, Kansas City, MO, USA.
  • Engleman K; Children's Mercy Hospital, Kansas City, MO, USA.
  • Racine C; 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.
  • Faivre L; 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.
  • Moutton S; 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.
  • Denommé-Pichon AS; 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.
  • Koh HY; 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.
  • Poduri A; Department of Neurology, Boston Children's Hospital, Boston, MA, USA.
  • Bolton J; Department of Neurology, Boston Children's Hospital, Boston, MA, USA.
  • Knopp C; Institute for Human Genetics and Genomic Medicine, Medical Faculty, RWTH, Aachen University, Aachen, Germany.
  • Julia Suh DS; Institute for Human Genetics and Genomic Medicine, Medical Faculty, RWTH, Aachen University, Aachen, Germany.
  • Maier A; Medical Treatment Center for Adults with Intellectual Disabilities and/or Severe Multiple Disabilities (MZEB), RWTH Aachen University Hospital, Aachen, Germany.
  • Toosi MB; Department of Pediatrics, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran; Neuroscience Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
  • Karimiani EG; 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.
  • Maroofian R; Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, UK.
  • Schaefer GB; University of Arkansas for Medical Sciences; Little Rock, AR, USA.
  • Ramakumaran V; LNR Genomics Medicine, University Hospitals of Leicester, Leicester, UK.
  • Vasudevan P; LNR Genomics Medicine, University Hospitals of Leicester, Leicester, UK.
  • Prasad C; London Health Sciences Centre, and Division of Medical Genetics, Department of Pediatrics, Western University, London, ON, Canada.
  • Osmond M; Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, ON, Canada.
Am J Hum Genet ; 111(1): 96-118, 2024 01 04.
Article en En | MEDLINE | ID: mdl-38181735
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.
Asunto(s)
Palabras clave

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Proteínas de Drosophila / Trastornos del Neurodesarrollo / Discapacidad Intelectual Límite: Adult / Animals / Humans Idioma: En Revista: Am J Hum Genet Año: 2024 Tipo del documento: Article

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Proteínas de Drosophila / Trastornos del Neurodesarrollo / Discapacidad Intelectual Límite: Adult / Animals / Humans Idioma: En Revista: Am J Hum Genet Año: 2024 Tipo del documento: Article