Image Credit: Scientific Frontline
Scientific Frontline: "At a Glance" Summary
- Main Discovery: Researchers identified a rare genetic mutation, C182F, within the TAAR1 brain receptor that completely negates the efficacy of newer schizophrenia treatments by structurally locking the receptor in an inactive state.
- Methodology: The study employed advanced cell biology assays and 500-nanosecond molecular dynamics simulations to analyze the variant, which was originally isolated from an Indian family with a history of schizophrenia.
- Key Data: In the homozygous state, the mutation caused a complete loss of receptor signaling function and reduced protein surface expression by approximately 40%, while heterozygous cells retained only about 50% activity.
- Significance: This discovery explains the clinical failure of promising TAAR1 agonists like ulotaront in certain patients, revealing that the mutation eliminates the critical disulfide bond "tent pole" needed for the drug to bind effectively.
- Future Application: Standard psychiatric care may evolve to include mandatory genetic screening for TAAR1 variants prior to prescribing specific antipsychotics to ensure alignment with the patient's pharmacogenomic profile.
- Branch of Science: Pharmacogenomics and Molecular Psychiatry.
- Additional Detail: While rare globally, the C182F mutation occurs more frequently in South Asian populations, highlighting a specific demographic necessity for targeted genetic testing in drug development.
Flinders University researchers have discovered a rare genetic mutation that could explain why some people do not respond to newer schizophrenia treatments.
The study, published in Genomic Psychiatry, reveals that an inherited change in the brain can completely block the function of the trace amine-associated receptor 1 (TAAR1), a receptor targeted by newer schizophrenia drugs making them ineffective.
Schizophrenia affects about 23 million people worldwide and is one of the hardest mental health conditions to manage. It can cause hallucinations, delusions, and problems with thinking and memory. Current medicines mostly work by targeting dopamine, but they are not effective for everyone and can cause serious side effects.
Principal Investigator of the study, Dr Pramod Nair, says that whilst TAAR1-based therapies have emerged as a leading alternative medication for treating schizophrenia, people with this mutation are unlikely to benefit from them.
“What surprised us most was how complete the effect was, the receptor didn’t just become weaker, it stopped responding altogether,” says Dr Nair who leads the Computational and Molecular Pharmacology laboratory at the College of Medicine and Public Health.
The study focused on a rare TAAR1 genetic variant, or mutation, known as C182F, first identified in an Indian family where the mother and two children were diagnosed with schizophrenia.
Using advanced cell biology techniques and molecular dynamics simulations, the team discovered that in normal TAAR1, a structural bond acts like a tent pole, holding the receptor’s binding pocket in the correct shape.
The C182F mutation removes this support and causes the receptor to fold in on itself, blocking the site where drugs and natural molecules would normally bind.
“The receptor basically locks itself shut and even the best new drugs can’t open it,” says Dr Nair.
“Our findings could explain why some people don’t respond to new schizophrenia treatments. While this mutation is very rare worldwide, it’s more common in South Asian populations.
“As TAAR1-based drugs move through clinical trials, genetic testing may become important to identify patients who won’t benefit.
“We need to think about screening for these mutations before treatment and use this information to help guide how trials are designed.”
The discovery also gives scientists new clues about what causes schizophrenia and highlights the need for personalized medicine, where treatment is tailored to a person’s genetic makeup.
Dr Nair says that this research is a big step forward in understanding how genes affect mental health and drug response and could help shape future treatments and improve care for people living with schizophrenia.
Funding: PCN acknowledges Flinders University and Southern Adelaide Local Health Network for Innovation Partnership Seed Funding. This study was supported by an Ideas Grant (2039377) from the National Health and Medical Research Council of Australia. This research was undertaken with the assistance of resources from the National Computational Infrastructure (NCI), which is supported by the Australian Government.
Published in journal: Genomic Psychiatry
Title: Functional implications of the C182F TAAR1 variant identified in patients with schizophrenia
Authors: Britto Shajan, Utsav Vaghasiya, Tarun Bastiampillai, Karen J. Gregory, and Shane D. Hellyer Article by Pramod C. Nair
Source/Credit: Flinders University
Reference Number: psyc020426_01