Our bodies are intricate systems, built from fundamental instructions contained within our DNA. These instructions are organized into units called genes, each serving as a blueprint for specific functions that contribute to our overall health and development. Among these, one particular gene, IRF2BPL, holds significance in understanding human biology and disease.
What is IRF2BPL?
IRF2BPL stands for Interferon Regulatory Factor 2 Binding Protein Like. Its name indicates a connection to interferon regulatory factors, proteins involved in the body’s immune response. The IRF2BPL gene is a segment of DNA located on human chromosome 14, at band 14q24.3. It carries the genetic information necessary for the production of a particular protein.
IRF2BPL is a protein-coding gene, meaning its primary function is to provide instructions for building a protein. It is an intron-less gene, meaning it does not contain non-coding regions that are typically spliced out. This characteristic can influence how the gene is expressed and how mutations within it might affect its function.
The Role of IRF2BPL in the Body
The IRF2BPL gene and the protein it produces are involved in regulating gene activity, acting as a transcription factor. This influences which genes are turned “on” or “off” within cells, a process that is fundamental to all biological functions. The protein encoded by IRF2BPL may also function as an E3 ubiquitin ligase. This process helps control protein levels and remove damaged or unneeded proteins within cells.
The IRF2BPL gene is expressed in many organs, including the central nervous system. It plays a role in the development and maintenance of neurons, which are the specialized cells of the brain and nervous system. Its involvement in neuronal maintenance is partly through the Wnt signaling pathway, which regulates cell proliferation, migration, differentiation, and synapse development in the central nervous system. This broad expression and involvement in cellular processes underscore its importance for normal body function, particularly in the brain.
When IRF2BPL Goes Wrong
When the IRF2BPL gene does not function correctly, typically due to genetic mutations, it can lead to a specific neurodevelopmental disorder. This condition is often referred to as IRF2BPL-related neurodevelopmental disorder, or by the acronym NEDAMSS (Neurodevelopmental Disorder with Regression, Abnormal Movements, Loss of Speech, and Seizures). Over 60 individuals have been identified with pathogenic variants in IRF2BPL. Symptoms of this disorder usually begin in childhood, sometimes as early as six months of life.
Individuals with IRF2BPL-related disorder often experience a range of neurological symptoms. These can include developmental delays, intellectual disability, and a regression or loss of previously acquired motor and language skills.
Movement difficulties are common, such as ataxia (uncoordinated movements), dystonia (involuntary muscle contractions), tremor, and hypotonia (low muscle tone). Speech impairment, including loss of speech, is also a frequently observed symptom. Seizures are reported in a significant number of affected individuals, with various types observed.
Brain changes, such as cerebral, cerebellar, or brainstem atrophy, can also be observed on magnetic resonance imaging (MRI). The severity of symptoms can vary depending on the specific type of IRF2BPL mutation, with nonsense mutations often leading to more severe outcomes.
Current Research and Future Directions
The diagnosis of IRF2BPL-related disorder is typically established through molecular genetic testing, often involving whole exome sequencing or whole genome sequencing. Genetic counseling is available, as the disorder is inherited in an autosomal dominant manner, though many cases arise from new, spontaneous mutations.
Scientists are actively researching IRF2BPL to understand the mechanisms by which mutations lead to symptoms. Efforts include developing animal models, such as fruit flies, to study the gene’s function and the effects of its malfunction. Additionally, three-dimensional (3D) brain organoids derived from patient cells are being explored to gain insights into how specific mutations affect neuronal development and function.
This research aims to identify pathways affected by the disease that could be targeted by pharmacological treatments. While there are currently no specific medicines designed to treat the syndrome, a genetic diagnosis helps guide management with therapies like physical, occupational, speech, or behavioral therapy. Collaborative research initiatives and patient registries, such as Simons Searchlight, are gathering data from affected individuals and their families to further understanding and accelerate the development of potential therapeutic strategies, including gene editing approaches.