Study Identifies Role of Gene Mutation in Previously Undiagnosed Neurological Disorder


Interferon regulatory factor 2 binding protein-like gene is essential for neurological development and maintenance.

New research has identified a potential disease-causing gene mutation that may be linked to neurological disorders, according to a study published in the American Journal of Human Genetics.

A team of scientists, including researchers from Baylor College of Medicine, investigated the effects of the gene mutation in 7 unrelated individuals with a previously undiagnosed neurological disorder.

They started by examining the DNA of a patient who presented with a severe neurological condition without a diagnosis. After sequencing the DNA of the patient and the patient’s family, the researchers found that mutation of the interferon regulatory factor 2 binding protein-like (IRF2BPL) gene could be a potential cause of the undiagnosed disorder, triggering progressive neurodegeneration. However, there is little understanding of the biological function of the gene, they noted.

Following the first patient, the researchers investigated the gene in 6 more patients presenting with similar neurological characteristics. Five of these patients were all born healthy, but exhibited an onset of symptoms indicating progressive, severe neurodevelopmental regression between the ages of 3 to 5 years old. This included lack of coordination, low muscle tone and muscle strength, and loss of full control of bodily movement. In the 2 other cases, the patients presented with milder characteristics, including global development delay and seizures.

The 5 patients with the most severe neurological condition carried a nonsense mutation of IRF2BPL, meaning a mutation that introduces a “stop” signal within the gene’s protein coding region, according to the researchers. The other 2 individuals carried a missense mutation, in which the mutation changed 1 single “letter” in the protein’s genetic code, resulting in the substitution of 1 amino acid for another in the protein made by the gene. The researchers also found that neither the nonsense or missense mutations were present in the patients’ parents.

To further investigate whether the gene candidate was associated with the human neurological disorder, the researchers tested it in fruit flies, targeting a gene called pits as the fruit fly’s equivalent of human IRF2BPL.

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The researchers found a common characteristic between the human and the fruit fly condition: both were a progressive type of neurodegeneration. The studies also indicated that the loss of pits was lethal to the fly’s early development, whereas partially knocking down pits resulted in neurodegeneration that progressively affected motor functions, the researchers wrote.

After genetically modifying the fruit flies to express the mutated IRF2BPL genes found in the patients, the researchers noted that the neurodegenerative effects seen in the patients were similarly observed in the flies.

“Taken together, our findings indicate that IRF2BPL 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,” study author Paul Marcogliese, PhD, postdoctoral associate of molecular and human genetics at Baylor, said in a press release. “Next, we want to find ways to improve or prevent the condition.”

The findings provide additional evidence that the IRF2BPL gene is necessary for proper neurological function and that loss of IRF2BPL can lead to a range of neurological effects. The researchers concluded that their next step is to investigate the mechanisms of the process that leads to neurodegeneration and develop a mouse model to test potential therapies.


Marcogliese PC, Pena L, et al. IRF2BPL is associated with neurological phenotypes. American Journal of Human Genetics. 2018. Doi:

Previously undiagnosed neurological disorder linked to mutations in gene IRF2BPL [news release]. Baylor College of Medicine’s website. Accessed July 30, 2018.

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