IRF2BPL Is Associated with Neurological Phenotypes

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.

EAP1 regulation of GnRH promoter activity is important for human pubertal timing

“…The affected members of these families displayed typical self-limited DP with late onset of puberty but full adult development by the age of 18 years. None of the affected individuals had neurological or other associated phenotypic abnormalities (23). Complementing previous studies in rats and non-human primates (7), we have shown that Eap1 is also abundantly expressed in the peri-pubertal mouse hypothalamus.…”

IRF2BPL gene mutation: Expanding on neurologic phenotypes

“…It is an intronless gene, formerly known as c 14orf4 . It encodes the interferon regulatory Factor 2‐binding protein‐like protein, a zinc finger/RING finger protein that functions as a transcriptional modulator (Macrogliese et al, ). In addition to transcriptional modulation, IRF2BPL functions as a E3 ubiquitin ligase that targets B‐catenin for proteasome degradation in gastric cancer (Higashimori et al, ).…”

“…In addition to transcriptional modulation, IRF2BPL functions as a E3 ubiquitin ligase that targets B‐catenin for proteasome degradation in gastric cancer (Higashimori et al, ). Studies of the orthologous gene, pits , in drosophila have demonstrated its importance in the nervous system and shown that truncated proteins are not hypermorphic or neomorphic and the disease mechanism likely involves loss of function (Macrogliese et al, ). The first clinical descriptions of individuals with IRF2BPL variants were published in 2018.…”

“…The first clinical descriptions of individuals with IRF2BPL variants were published in 2018. While the phenotype is varied, it has been associated with developmental regression in childhood as well as epilepsy (Macrogliese et al, ; Skorvanek et al, ; Tran Mau‐Them et al, ).…”

Pits and CtBP control tissue growth in Drosophila melanogaster with the Hippo pathway transcription repressor, Tgi

“…This is consistent with a recent study that used imprecise P-element excision to generate three pits alleles, two of which were homozygous viable, whilst the third was semi-lethal (LIAW 2016). An independent study used recombination mediated cassette exchange to generate pits mutant alleles, which were hemizygous lethal (MARCOGLIESE et al 2018). We utilised our pits mutant alleles to further test whether Tgi requires pits to retard eye growth.…”