Scientists have discovered a new genetic disease that causes abnormal brain growth in some children and delays intellectual development. Most people with this disease, which is still so new it doesn’t have a name, have significant learning difficulties that have a negative impact on their quality of life. According to an international team of researchers from the universities of Portsmouth, Southampton and Copenhagen, the underlying cause of this unusual genetic disorder was changes in the gene encoding a protein known as glutamate ionotropic AMPA receptor type 1 subunit (GRIA1).
The discovery of this variant will help doctors develop targeted treatments to help patients and their families, and pave the way for screening and prenatal diagnosis.The GRIA1 gene facilitates the movement of electrical impulses within the brain. The brain’s ability to remember information can be impaired if this process is disrupted or less efficient.
To demonstrate that GRIA1 mutations are the underlying cause of the behavior-altering disease, the study team – which consists of frog geneticists, biochemists and clinical geneticists – used tadpoles in which the human gene changes had been replicated using gene editing. Biochemical analysis of the variants was also performed on frog oocytes.The results were published in the American Journal of Human Genetics.
Study co-author Professor Matt Guille, who leads the laboratory in the Epigenetics and Developmental Biology Research Group at the University of Portsmouth, said: “Next generation DNA sequencing is transforming our ability to make new diagnoses and discover new genetic causes of rare disorders.
“The main obstacle in providing diagnoses for these patients is firmly linking the discovered change in their genome to their disease. Creating the suspected genetic change in tadpoles allows us to test whether it causes the same disease in humans.The resulting data allows us to support our colleagues in providing the more timely and accurate diagnosis that patients and their families so desperately need.”
Co-author Dr. Annie Goodwin, a researcher at the University of Portsmouth who carried out much of the study, said: “This has been transformative work for us; the ability to analyze human-like behavior in tadpoles with sufficient precision to detect disease-related genetic changes opens up the opportunity to help identify a wide range of diseases. This is particularly important given that so many neurodevelopmental disorders are currently undiagnosed.”
Co-author Professor Diana Baralle, Professor of Genomic Medicine and Vice-Dean (Research) at the University of Southampton School of Medicine, added: “The discovery of these new causes of genetic disorders ends the diagnostic odyssey for our patients and has enabled interdisciplinary collaboration across universities.”One in 17 people will suffer from a rare disease at some point in their life. Most of these rare diseases have a genetic cause and often affect children, but proving which gene change causes the disease is a huge challenge.
Professor Guille said that previously, while studies linking the gene and the disease were mainly carried out in mice; several laboratories, including his own at the University of Portsmouth, have recently shown that tadpole experiments can also provide very strong evidence for the function of variant human genes. The process of recreating some gene variants in tadpoles is straightforward and can be done in as little as three days. Professor Guille added: “We are currently expanding and improving our technology in a program funded by the Medical Research Council; this makes it applicable to a wider range of disease-related DNA alterations provided to us by our clinical collaborators. “If clinical researchers find the information sufficiently useful, we will continue to work together to expand the gene function analysis pipeline so that it can be used to direct effective interventions in a significant number of patients.”
For more read: Vardha Ismail et al, Identification and functional evaluation of GRIA1 missense and truncation variants in individuals with ID: An emerging neurodevelopmental syndrome” June 2022, American Journal of Human Genetics. DOI: 10.1016/j.ajhg.2022.05.009
