Researchers at the Indian Institute of Technology (IIT), Madras, Tel Aviv University and Columbia University are studying a rare genetic brain disease called "GNB1 Encephalopathy" and trying to develop a drug to treat it effectively.
With less than 100 documented cases worldwide, GNB1 Encephalopathy is a kind of neurological disorder which affects individuals in the foetus stage.
Scientists say delayed physical and mental development, intellectual disabilities, frequent epileptic seizures, are among the early symptoms of the disease and since genome-sequencing is an expensive procedure, not many parents opt for it early on.
According to Haritha Reddy, a former PhD scholar at IIT Madras, a single nucleotide mutation in the GNB1 gene that makes one of the G-proteins, the "Gβ1 protein," causes this disease.
"This mutation affects the patient since they are a foetus. Children born with GNB1 mutation experience mental and physical developmental delay, epilepsy (abnormal brain activity), movement problems. To date, less than a hundred cases have been documented worldwide.
"However, the actual number of affected children is probably much greater as diagnosis is not widely available since it requires a sophisticated and expensive procedure," Reddy told PTI from Israel, where she is conducting the research.
"Every cell in the human body has a wide variety of signalling molecules and pathways that help in communicating with other cells and within itself. The major signalling mechanism used by cells is 'G-Protein Coupled Receptor' (GPCR) signalling," she added.
The GPCR is a receptor that receives a signal (e.g. a hormone, light, neurotransmitter) from the outside of the cell and transduces it to the inside of the cell.
"GPCR is present in the cell membrane and has a G-protein (αβγ) attached to it from inside the cell. G-proteins are the immediate downstream molecules that relay the signal received by the GPCR. These G-proteins are present in every cell, and any malfunction will cause disease," she explained.
Mutations in GNB1 gene cause the neurological disorder (GNB1 Encephalopathy) characterised by general develop- mental delay, epileptiform activity in the electroencephalogram (EEG) and seizures of several types, muscle hypotonia or hypertonia, and additional variable symptoms, are seen in the patients.
According to Amal Kanti Bera, Professor, Department of Biotechnology, IIT Madras, as GNB1 encephalopathy is a rare and less-known disease, not much research has been done on this.
"We don't know the mechanisms that underlie the disease. We don't know how to treat this disease. Therefore, it is import to do research on GNB1 encephalopathy.We have a long way to go. It is not easy to develop a drug for treating this disease effectively," he told PTI.
"We are in the process of developing preclinical animal models of this disease. Hopefully, in three years we will be able to develop personalised disease models which will be useful in research and drug screening," he told PTI.
The strong neurological impact of GNB1 mutations indicates that Gβ1 is involved in specific aspects of neuronal signaling. A recent proteomic study identified strong link between human epilepsies and Gβ1 protein levels in different brain regions.
Nathan Dascal, Professor, Tel Aviv University, explained that as the developmental issues start at the fetal stage, gene therapy is the most plausible option to alleviate the effects of the mutation. However, the development of this complicated procedure will take many years and great investment of funds.
"On the other hand, epilepsy can be treated using specific drugs to increase the patient's quality of life. To treat epilepsy, specific targets have to be identified. Most epilepsies are caused due to altered ion channel function. Ion channels are proteins that underlie the electrical activity of neurons and heart cells.
"It is also possible that a combination of already existing drugs helps in a customised treatment line for the rare disease. Like in case of Covid, no new drug was found but already available drugs became part of treatment protocol," he said.
The research was supported by Indo-Israel Binational grant offered by Israel Science Foundation (ISF) and India's University Grants Commission (UGC).
Professor Dascal pointed out that whole genome sequencing, the elucidation of the full genetic analysis of the baby, can be very helpful in early diagnosis of the disease.
"We have found that a potassium channel called G-protein gated Inwardly Rectifying K (GIRK) channel (present in brain, heart and endocrine glands) function is affected significantly. Then we used specific drugs to correct the channel activity.
"As I80T mutation is the most prevalent variant in GNB1 encephalopathy patients, we are currently focusing prioritising on this mutation alone. We have a mouse models with I80T, K78R and D76G mutations. We have generated induced pluripotent stem cells (iPSCs) from the patient's fibroblasts with I80T mutation.
"We will differentiate patient-derived iPSCs to differentiate into neurons. Our study paves the way for testing in animal models or patient-derived neurons to develop concrete therapeutic approaches," he said.
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