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Am J Hum Genet. 2018 Aug 2;103(2):245-260. doi: 10.1016/j.ajhg.2018.07.006. Epub 2018 Jul 26.

IRF2BPL Is Associated with Neurological Phenotypes.

Collaborators (175)

Callens S, Coucke P, Dermaut B, Hemelsoet D, Poppe B, Steyaert W, Terryn W, Van Coster R, Adams DR, Alejandro ME, Allard P, Azamian MS, Bacino CA, Balasubramanyam A, Barseghyan H, Batzli GF, Beggs AH, Behnam B, Bican A, Bick DP, Birch CL, Bonner D, Boone BE, Bostwick BL, Briere LC, Brown DM, Brush M, Burke EA, Burrage LC, Chen S, Clark GD, Coakley TR, Cogan JD, Cooper CM, Cope H, Craigen WJ, D'Souza P, Davids M, Dayal JG, Dell'Angelica EC, Dhar SU, Dillon A, Dipple KM, Donnell-Fink LA, Dorrani N, Dorset DC, Douine ED, Draper DD, Eckstein DJ, Emrick LT, Eng CM, Eskin A, Esteves C, Estwick T, Ferreira C, Fogel BL, Friedman ND, Gahl WA, Glanton E, Godfrey RA, Goldstein DB, Gould SE, Gourdine JF, Groden CA, Gropman AL, Haendel M, Hamid R, Hanchard NA, Handley LH, Herzog MR, Holm IA, Hom J, Howerton EM, Huang Y, Jacob HJ, Jain M, Jiang YH, Johnston JM, Jones AL, Kohane IS, Krasnewich DM, Krieg EL, Krier JB, Lalani SR, Lau CC, Lazar J, Lee BH, Lee H, Levy SE, Lewis RA, Lincoln SA, Lipson A, Loo SK, Loscalzo J, Maas RL, Macnamara EF, MacRae CA, Maduro VV, Majcherska MM, Malicdan MCV, Mamounas LA, Manolio TA, Markello TC, Marom R, Martínez-Agosto JA, Marwaha S, May T, McConkie-Rosell A, McCormack CE, McCray AT, Might M, Moretti PM, Morimoto M, Mulvihill JJ, Murphy JL, Muzny DM, Nehrebecky ME, Nelson SF, Newberry JS, Newman JH, Nicholas SK, Novacic D, Orange JS, Pallais JC, Palmer CGS, Papp JC, Parker NH, Pena LDM, Phillips JA 3rd, Posey JE, Postlethwait JH, Potocki L, Pusey BN, Reuter CM, Robertson AK, Rodan LH, Rosenfeld JA, Sampson JB, Samson SL, Schoch K, Schroeder MC, Scott DA, Sharma P, Shashi V, Signer R, Silverman EK, Sinsheimer JS, Smith KS, Spillmann RC, Splinter K, Stoler JM, Stong N, Sullivan JA, Sweetser DA, Tifft CJ, Toro C, Tran AA, Urv TK, Valivullah ZM, Vilain E, Vogel TP, Wahl CE, Walley NM, Walsh CA, Ward PA, Waters KM, Westerfield M, Wise AL, Wolfe LA, Worthey EA, Yamamoto S, Yang Y, Yu G, Zastrow DB, Zheng A.

Author information

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.

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

PMID:
30057031
PMCID:
PMC6081494
[Available on 2019-02-02]
DOI:
10.1016/j.ajhg.2018.07.006

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