IRF2BPL Is Associated with Neurological Phenotypes

Program for Undiagnosed Diseases (UD-PrOZA), Undiagnosed Diseases Network

Research output: Contribution to journalArticle

10 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)245-260
Number of pages16
JournalAmerican Journal of Human Genetics
Volume103
Issue number2
DOIs
StatePublished - Aug 2 2018

Fingerprint

Interferon Regulatory Factor-2
Carrier Proteins
Phenotype
Ataxia
Diptera
Nervous System
Genes
Seizures
Alleles
Metagenomics
Muscle Hypotonia
Nonsense Codon
RNA Interference
Computational Biology
Fruit
Maintenance
Neurons

Keywords

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

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Program for Undiagnosed Diseases (UD-PrOZA), & Undiagnosed Diseases Network (2018). IRF2BPL Is Associated with Neurological Phenotypes. American Journal of Human Genetics, 103(2), 245-260. https://doi.org/10.1016/j.ajhg.2018.07.006

IRF2BPL Is Associated with Neurological Phenotypes. / Program for Undiagnosed Diseases (UD-PrOZA); Undiagnosed Diseases Network.

In: American Journal of Human Genetics, Vol. 103, No. 2, 02.08.2018, p. 245-260.

Research output: Contribution to journalArticle

Program for Undiagnosed Diseases (UD-PrOZA) & Undiagnosed Diseases Network 2018, 'IRF2BPL Is Associated with Neurological Phenotypes', American Journal of Human Genetics, vol. 103, no. 2, pp. 245-260. https://doi.org/10.1016/j.ajhg.2018.07.006
Program for Undiagnosed Diseases (UD-PrOZA), Undiagnosed Diseases Network. IRF2BPL Is Associated with Neurological Phenotypes. American Journal of Human Genetics. 2018 Aug 2;103(2):245-260. https://doi.org/10.1016/j.ajhg.2018.07.006
Program for Undiagnosed Diseases (UD-PrOZA) ; Undiagnosed Diseases Network. / IRF2BPL Is Associated with Neurological Phenotypes. In: American Journal of Human Genetics. 2018 ; Vol. 103, No. 2. pp. 245-260.
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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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AU - Shashi, Vandana

AU - Spillmann, Rebecca C.

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AU - Zuo, Zhongyuan

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AU - Xia, Fan

AU - Yang, Yaping

AU - Smith, Edward C.

AU - Jasien, Joan

AU - Kansagra, Sujay

AU - Spiridigliozzi, Gail

AU - El-Dairi, Mays

AU - Lark, Robert

AU - Riley, Kacie

AU - Koeberl, Dwight D.

AU - Golden-Grant, Katie

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AU - Coucke, Paul

AU - Dermaut, Bart

AU - Hemelsoet, Dimitri

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N2 - 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.

AB - 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.

KW - ataxia

KW - C3HC4 RING finger

KW - CG11138

KW - developmental regression

KW - Drosophila

KW - EAP1

KW - hypotonia

KW - neurodegeneration

KW - pits

KW - seizures

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