A newly identified genetic disease, yet unnamed, is characterized by such severe, delayed intellectual development that a child and family suffer loss of quality of life. Identification of the variant will help in the development of focused interventions for both patients and their families.
Researchers report that changes in a protein coding gene called Glutamate Ionotropic Receptor AMPA Type Subunit 1 (GRIA1) causes the rare genetic disorder. Scientists from the universities of Portsmouth and Southampton in England, and the University of Copenhagen in Denmark, collaborated on the study.
The GRIA1 gene encodes proteins which enable transmission of electrical signals throughout the brain. If this process is interrupted or rendered inefficient, it can reduce the brain’s ability to retain information.
The research team included frog geneticists, biochemists, and clinical geneticists. Using tadpoles with gene variants which mimic the relevant human gene variants, they show that changes in the GRIA1 are the underlying cause of the intellect-altering disease.
“Next generation DNA sequencing is transforming our ability to discover new genetic causes of rare disorders,” says study co-author Matt Guille, leader of the Epigenetics and Developmental Biology research group in a statement.
“The main bottleneck in providing diagnoses for these patients is linking a change discovered in their genome firmly to their disease. Making the suspect genetic change in tadpoles allows us to test whether it causes the same illness in humans,” he continues. “The resulting data allow us to support our colleagues in providing the more timely, accurate diagnoses that patients and their families so desperately need.”
Adds Dr. Annie Goodwin, also from Portsmouth, who performed much of the study: “This was a transformational piece of work for us. The ability to analyze human-like behaviors in tadpoles with sufficient accuracy to detect genetic disease-linked changes opens the opportunity to help identify a huge range of diseases. This is particularly important given that so many neurodevelopmental diseases are currently undiagnosed.”
One in 17 people will suffer from a rare disease at some time in their lives. Most of these rare diseases have a genetic cause and often affect children. Connecting a specific gene to a specific disease is labor-intensive work.
Previous studies which connected a gene with a disorder were performed in mice. Several labs, including the University of Portsmouth, have recently shown that tadpoles can also be used to mimic the functions of variant human genes. Creating some gene variants in tadpoles is straightforward and can be done in as little as three days.
“We are currently expanding and improving our technology, making it applicable to a wider range of disease-related DNA changes provided to us by our clinical collaborators,” adds Guille. “If the clinical researchers find the information sufficiently useful, then we will continue to work together to scale up the pipeline of gene function analysis so it can be used to develop effective interventions for a significant number of patients.”
The study is published in the journal Genome Medicine.