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IRF2BPL Is Associated with Neurological Phenotypes.
Marcogliese, Paul C; Shashi, Vandana; Spillmann, Rebecca C; Stong, Nicholas; Rosenfeld, Jill A; Koenig, Mary Kay; Martínez-Agosto, Julián A; Herzog, Matthew; Chen, Agnes H; Dickson, Patricia I; Lin, Henry J; Vera, Moin U; Salamon, Noriko; Graham, John M; Ortiz, Damara; Infante, Elena; Steyaert, Wouter; Dermaut, Bart; Poppe, Bruce; Chung, Hyung-Lok; Zuo, Zhongyuan; Lee, Pei-Tseng; Kanca, Oguz; Xia, Fan; Yang, Yaping; Smith, Edward C; Jasien, Joan; Kansagra, Sujay; Spiridigliozzi, Gail; El-Dairi, Mays; Lark, Robert; Riley, Kacie; Koeberl, Dwight D; Golden-Grant, Katie; Yamamoto, Shinya; Wangler, Michael F; Mirzaa, Ghayda; Hemelsoet, Dimitri; Lee, Brendan; Nelson, Stanley F; Goldstein, David B; Bellen, Hugo J; Pena, Loren D M.
  • Marcogliese PC; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
  • Shashi V; Division of Medical Genetics, Department of Pediatrics, Duke University School of Medicine, Durham, NC 27710, USA.
  • Spillmann RC; Division of Medical Genetics, Department of Pediatrics, Duke University School of Medicine, Durham, NC 27710, USA.
  • Stong N; Institute for Genomic Medicine, Columbia University Medical Center, New York, NY 10032, USA.
  • Rosenfeld JA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
  • Koenig MK; Division of Child & Adolescent Neurology, Department of Pediatrics, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
  • Martínez-Agosto JA; Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Pediatrics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Child and Adolescent Psychiatr
  • Herzog M; Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
  • Chen AH; Department of Pediatrics, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA 90502, USA.
  • Dickson PI; Department of Pediatrics, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA 90502, USA.
  • Lin HJ; Department of Pediatrics, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA 90502, USA.
  • Vera MU; Department of Pediatrics, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA 90502, USA.
  • Salamon N; Department of Radiology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
  • Graham JM; Department of Pediatrics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
  • Ortiz D; Children's Hospital of Pittsburgh, University of Pittsburgh Medical Center, University of Pittsburgh, Pittsburgh, PA 15224, USA.
  • Infante E; Children's Hospital of Pittsburgh, University of Pittsburgh Medical Center, University of Pittsburgh, Pittsburgh, PA 15224, USA.
  • Steyaert W; Department of Medical Genetics, Ghent University Hospital, 9000 Ghent, Belgium.
  • Dermaut B; Department of Medical Genetics, Ghent University Hospital, 9000 Ghent, Belgium.
  • Poppe B; Department of Medical Genetics, Ghent University Hospital, 9000 Ghent, Belgium.
  • Chung HL; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
  • Zuo Z; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
  • Lee PT; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
  • Kanca O; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
  • Xia F; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
  • Yang Y; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
  • Smith EC; Division of Neurology, Department of Pediatrics, Duke University School of Medicine, Durham, NC 27710, USA.
  • Jasien J; Division of Neurology, Department of Pediatrics, Duke University School of Medicine, Durham, NC 27710, USA.
  • Kansagra S; Division of Neurology, Department of Pediatrics, Duke University School of Medicine, Durham, NC 27710, USA.
  • Spiridigliozzi G; Department of Psychiatry and Behavioral Sciences, Duke University School of Medicine, Durham, NC 27710, USA.
  • El-Dairi M; Department of Ophthalmology, Duke University School of Medicine, Durham, NC 27710, USA.
  • Lark R; Department of Orthopedic Surgery, Duke University School of Medicine, Durham, NC 27710, USA.
  • Riley K; Division of Medical Genetics, Department of Pediatrics, Duke University School of Medicine, Durham, NC 27710, USA.
  • Koeberl DD; Division of Medical Genetics, Department of Pediatrics, Duke University School of Medicine, Durham, NC 27710, USA.
  • Golden-Grant K; Division of Genetic Medicine, Seattle Children's Hospital, Seattle, WA 98105, USA.
  • Yamamoto S; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Program in Developmental Biology, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX 77030, USA; Department of N
  • Wangler MF; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Program in Developmental Biology, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX 77030, USA.
  • Mirzaa G; Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA 98105, USA; Department of Pediatrics, University of Washington, Seattle, WA 98105, USA.
  • Hemelsoet D; Department of Neurology, Ghent University Hospital, 9000 Ghent, Belgium.
  • Lee B; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
  • Nelson SF; Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
  • Goldstein DB; Institute for Genomic Medicine, Columbia University Medical Center, New York, NY 10032, USA.
  • Bellen HJ; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Program in Developmental Biology, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX 77030, USA; Department of N
  • Pena LDM; Division of Medical Genetics, Department of Pediatrics, Duke University School of Medicine, Durham, NC 27710, USA. Electronic address: loren.pena@cchmc.org.
Am J Hum Genet ; 103(2): 245-260, 2018 08 02.
Article en En | MEDLINE | ID: mdl-30057031
ABSTRACT
Interferon regulatory factor 2 binding protein-like (IRF2BPL) encodes a member of the IRF2BP family of transcriptional regulators. Currently the biological function of this gene is obscure, and the gene has not been associated with a Mendelian disease. Here we describe seven individuals who carry damaging heterozygous variants in IRF2BPL and are affected with neurological symptoms. Five individuals who carry IRF2BPL nonsense variants resulting in a premature stop codon display severe neurodevelopmental regression, hypotonia, progressive ataxia, seizures, and a lack of coordination. Two additional individuals, both with missense variants, display global developmental delay and seizures and a relatively milder phenotype than those with nonsense alleles. The IRF2BPL bioinformatics signature based on population genomics is consistent with a gene that is intolerant to variation. We show that the fruit-fly IRF2BPL ortholog, called pits (protein interacting with Ttk69 and Sin3A), is broadly detected, including in the nervous system. Complete loss of pits is lethal early in development, whereas partial knockdown with RNA interference in neurons leads to neurodegeneration, revealing a requirement for this gene in proper neuronal function and maintenance. The identified IRF2BPL nonsense variants behave as severe loss-of-function alleles in this model organism, and ectopic expression of the missense variants leads to a range of phenotypes. Taken together, our results show that IRF2BPL and pits are required in the nervous system in humans and flies, and their loss leads to a range of neurological phenotypes in both species.
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Texto completo: 1 Banco de datos: MEDLINE Tipo de estudio: Prognostic_studies / Risk_factors_studies Idioma: En Año: 2018 Tipo del documento: Article
Texto completo
Imprimir
XML
PubMed Links
Search on Google

Texto completo: 1 Banco de datos: MEDLINE Tipo de estudio: Prognostic_studies / Risk_factors_studies Idioma: En Año: 2018 Tipo del documento: Article