Researchers discover new neurological disease associated with IRF2BPL mutations

By Naveed Saleh, MD, MS, for MDLinx
Published September 17, 2018

Key Takeaways

Mutations in interferon regulatory factor 2 binding protein-like gene, or IRF2BPL, have been associated with a novel neurological disorder in seven unrelated individuals, according to a new study in the American Journal of Human Genetics.

“Our findings offer additional evidence that variants in IRF2BPL are implicated in neurological symptoms, and they additionally extend the phenotype into neurodevelopmental regression,” wrote authors, co-led by Hugo J. Bellen, DVM, PhD, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX. “Furthermore, our model-organism experiments with fruit flies support an important role for IRF2BPL in embryologic development as well as neuronal maintenance.”

Emerging evidence has pointed to new associations between genes and severe developmental conditions, as well as neurodegeneration. These associations have been discovered due mostly to advances in technology, including high-throughput sequencing methods (such as next generation sequencing), sequencing databases for control cohorts, variant prediction, model organism information, and crowdsourcing programs.

IRF2BPL codes for a member of the IRF2BP family of transcriptional regulators. The in vivo function of IRF2BPL has yet to be fully elucidated. In humans, this gene has not previously been associated with Mendelian disease.

“We provide evidence in seven individuals and use functional assays in fruit flies to support the findings that these variants cause dramatic changes to IRF2BPL function and that IRF2BPL plays a role in both development and neuronal maintenance,” the authors wrote.

Dr. Bellen and colleagues examined seven subjects who harbored harmful heterozygous IRF2BPL variants and exhibited neurological symptoms.

Five patients carried IRF2BPL nonsense variants that yielded a premature stop codon. They exhibited severe neurodevelopmental regression, hypotonia, progressive ataxia, seizures, and a lack of coordination. The other two patients harbored missense variants and exhibited a milder phenotype characterized by global developmental delay, seizures, and autism spectrum disorder.

The team found that the bioinformatics signature of IRF2BPL based on population genomics is intolerant to variation. The gene variants observed among study subjects are among the most damaging.

“We demonstrated that IRF2BPL de novo predicted damaging variants are overrepresented in individuals with neurodevelopmental phenotypes,” the investigators wrote. “The DOMINO score was suggestive of dominant inheritance.”

On a related note, findings from one recent population study have indicated that de novo genomic contributions amounted to approximately 42% of the cohort-carried pathogenic de novo mutations in the coding region of genes.

The team also found that the absence of nonsense-mediated decay of IRF2BPL transcript with a nonsense mutation supports the fact that this gene is a single exon.

In fruit flies, the team found that the IRF2BL ortholog, also called pits, is widespread, including at the level of the nervous system. Early loss of pits is deadly during fruit fly development. Partial knockdown of pits yielded neurodegeneration that progressively impacted motor functions over time, suggesting that this gene is required for normal neuronal function. In these insect models, IRF2BL nonsense variants acted as severe loss-of-function alleles, and ectopic missense mutations of this gene resulted in a gambit of phenotypes.

"Taken together, our findings indicate that IRB2BPL and pits are essential genes for the nervous system of both humans and fruit flies and their loss or disruption results in a variety of neurological conditions," reflected study author Paul C. Marcogliese, PhD, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston. "Next, we want to find ways to improve or prevent the condition."

Dr. Bellen laid out their plans for the future: "Our next goals are to work with fruit flies to study the biology of the process that leads to neurodegeneration and to develop a mouse model of the human condition in which we could test potential therapies.”

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