Author:
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,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.,
Abstract
AbstractThe Interferon Regulatory Factor 2 Binding Protein Like (IRF2BPL) gene 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 affected with neurological symptoms who carry damaging heterozygous variants in IRF2BPL. Five cases carrying nonsense variants in IRF2BPL 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 bioinformatics signature for IRF2BPL based on population genomics is consistent with a gene that is intolerant to variation. We show that the IRF2BPL ortholog in the fruit fly, called pits (protein interacting with Ttk69 and Sin3A), is broadly expressed including the nervous system. Complete loss of pits is lethal early in development, whereas partial knock-down with RNA interference in neurons leads to neurodegeneration, revealing requirement for this gene in proper neuronal function and maintenance. The nonsense variants in IRF2BPL identified in patients behave as severe loss-of-function alleles in this model organism, while ectopic expression of the missense variants leads to a range of phenotypes. Taken together, 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.
Publisher
Cold Spring Harbor Laboratory
Cited by
3 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献