2. Academic Validation
  3. IRF2BPL Is Associated with Neurological Phenotypes

IRF2BPL Is Associated with Neurological Phenotypes

  • Am J Hum Genet. 2018 Aug 2;103(2):245-260. doi: 10.1016/j.ajhg.2018.07.006.
Paul C Marcogliese 1,  Vandana Shashi 2,  Rebecca C Spillmann 2,  Nicholas Stong 3,  Jill A Rosenfeld 1,  Mary Kay Koenig 4,  Julián A Martínez-Agosto 5,  Matthew Herzog 6,  Agnes H Chen 7,  Patricia I Dickson 7,  Henry J Lin 7,  Moin U Vera 7,  Noriko Salamon 8,  John M Graham Jr 9,  Damara Ortiz 10,  Elena Infante 10,  Wouter Steyaert 11,  Bart Dermaut 11,  Bruce Poppe 11,  Hyung-Lok Chung 1,  Zhongyuan Zuo 1,  Pei-Tseng Lee 1,  Oguz Kanca 1,  Fan Xia 1,  Yaping Yang 1,  Edward C Smith 12,  Joan Jasien 12,  Sujay Kansagra 12,  Gail Spiridigliozzi 13,  Mays El-Dairi 14,  Robert Lark 15,  Kacie Riley 2,  Dwight D Koeberl 2,  Katie Golden-Grant 16,  Program for Undiagnosed Diseases (UD-PrOZA),  Undiagnosed Diseases Network,  Shinya Yamamoto 17,  Michael F Wangler 18,  Ghayda Mirzaa 19,  Dimitri Hemelsoet 20,  Brendan Lee 1,  Stanley F Nelson 6,  David B Goldstein 3,  Hugo J Bellen 21,  Loren D M Pena 22
Affiliations

Affiliations

  • 1 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
  • 2 Division of Medical Genetics, Department of Pediatrics, Duke University School of Medicine, Durham, NC 27710, USA.
  • 3 Institute for Genomic Medicine, Columbia University Medical Center, New York, NY 10032, USA.
  • 4 Division of Child & Adolescent Neurology, Department of Pediatrics, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
  • 5 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 Psychiatry, Resnick Neuropsychiatric Hospital, University of California, Los Angeles, Los Angeles, CA 90095, USA.
  • 6 Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
  • 7 Department of Pediatrics, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA 90502, USA.
  • 8 Department of Radiology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
  • 9 Department of Pediatrics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
  • 10 Children's Hospital of Pittsburgh, University of Pittsburgh Medical Center, University of Pittsburgh, Pittsburgh, PA 15224, USA.
  • 11 Department of Medical Genetics, Ghent University Hospital, 9000 Ghent, Belgium.
  • 12 Division of Neurology, Department of Pediatrics, Duke University School of Medicine, Durham, NC 27710, USA.
  • 13 Department of Psychiatry and Behavioral Sciences, Duke University School of Medicine, Durham, NC 27710, USA.
  • 14 Department of Ophthalmology, Duke University School of Medicine, Durham, NC 27710, USA.
  • 15 Department of Orthopedic Surgery, Duke University School of Medicine, Durham, NC 27710, USA.
  • 16 Division of Genetic Medicine, Seattle Children's Hospital, Seattle, WA 98105, USA.
  • 17 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 Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA.
  • 18 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.
  • 19 Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA 98105, USA; Department of Pediatrics, University of Washington, Seattle, WA 98105, USA.
  • 20 Department of Neurology, Ghent University Hospital, 9000 Ghent, Belgium.
  • 21 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 Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA; Howard Hughes Medical Institute, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address: hbellen@bcm.edu.
  • 22 Division of Medical Genetics, Department of Pediatrics, Duke University School of Medicine, Durham, NC 27710, USA. Electronic address: loren.pena@cchmc.org.
PMID: 30057031 DOI: 10.1016/j.ajhg.2018.07.006
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.

Keywords

C3HC4 RING finger; CG11138; Drosophila; EAP1; ataxia; developmental regression; hypotonia; neurodegeneration; pits; seizures.

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