Previously undiagnosed neurological disorder linked to mutations in gene IRF2BPL
Connecting gene IRF2BPL with an undiagnosed neurological disorder
The researchers’ investigations showed that the five individuals presenting 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. This type of mutation results in the production of a truncated protein that usually cannot fulfill the function of the normal protein.
The two individuals presenting with milder neurological conditions, on the other hand, carry a missense mutation. In this case, the mutation changed one single ‘letter’ in the protein’s genetic code resulting in the substitution of one amino acid – the building blocks of proteins – for another in the protein made by the gene. Both the nonsense and the missense mutations are de novo, or new in the patients, meaning they are not present in their parents. The mutations also are dominant; only one of the two copies of the gene is defective in the patients, and this is sufficient to cause disease.
To learn more about gene IRF2BPL that could connect it to the human neurological disorder, the researchers carried out experiments in the fruit fly. This animal model expresses a gene called pits, which is the fruit fly’s equivalent of human IRF2BPL.
“Our studies showed that the gene known as pits is broadly expressed in the fruit fly’s brain,” said Bellen, who also is a member of the Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital. “Complete loss of pits was lethal in the fly’s early development. Interestingly, we found that partially knocking down pits resulted in neurodegeneration that progressively affected motor functions as the flies aged. So, one common characteristic between the human and the fly condition is that both are a progressive type of neurodegeneration.”
The researchers also looked into what was going on at the cellular level, specifically the consequences of knocking down pits only in the light-sensitive neurons or photoreceptors in the fruit fly’s eyes.
“We observed that the photoreceptors are fine while the flies are young, but show signs of degeneration in the aged flies,” Marcogliese said. “Electron microscopy studies revealed a number of altered cellular structures and the accumulation of lipid droplets, which are known to negatively affect neuronal function.”
In addition, the researchers genetically modified fruit flies to express the mutated IRF2BPL genes found in the patients. Expressing the severe nonsense mutations in flies resulted in a drastic loss of function and expression of one of the missense mutations that causes a more subtle neurological condition in humans resulted in a partial loss of function in the flies.
“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,” Marcogliese said. “Next, we want to find ways to improve or prevent the condition.”
“The clinician-researcher partnership was particularly exciting, as the work on fruit flies provided additional compelling evidence that IRF2BPL is an important protein for neurological development and maintenance,” said Pena. “The work on fruit flies also was crucial in providing information to classify the variants in IRF2BPL as a likely diagnosis.”
“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,” Bellen said.
For the full list of contributors and their affiliation, visit this link.
This work was funded by the Undiagnosed Diseases Network U01HG007672, U01HG007703 and U54NS093793; R01GM067858 and R24OD022005 grants and a Simons Foundation Functional Screen Award (368479). Further support was provided by the National Institute of Neurological Disorders and Stroke under award number K08NS092898, the Jordan's Guardian Angels, and grant U54HD083092 to the Intellectual and Developmental Disabilities Research Center (IDDRC) Neurovisualization Core.