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New research, published today, has defined the functional impacts of hundreds of variants in a gene that is a major cause of neurodevelopmental disorders.

Predicted impact of missense variants on GABA uptake across the entire SLC6A1 gene

Haploinsufficiency underlies the neurodevelopmental consequences of SLC6A1 variants, published in The American Journal of Human Genetics, demonstrates that seizures, developmental delay, and autism spectrum disorder are caused by a decrease in GABA uptake by the protein encoded by the SLC6A1 gene. This provides clear direction for future therapeutic strategies for neurodevelopmental disorders linked to SLC6A1, which should aim to increase SLC6A1 expression or improve GABA uptake. It also provides data to help guide clinicians in making future diagnoses for variants in this gene.

GABA, or Gamma-aminobutyric acid, is a neurotransmitter, a brain chemical that sends messages throughout the central nervous system. GABA usually acts in an inhibitory manner, making the neuron that receives it less likely to fire.

Stephan Sanders, Professor of Paediatric Neurogenetics at the University of Oxford, who co-led the research, said: “By performing a comprehensive functional screen of variants in SLC6A1, our two groups independently saw that a reduction in GABA uptake underlies both neurodevelopmental and seizure symptoms. This is a key initial step in developing therapies to improve symptoms.”

The research also explored why many of the SLC6A1 variants seen in symptomatic individuals are missense variants. The gene SLC6A1 contains the genetic information to make a GABA transporter protein called GAT-1. Missense variants are those in which a change in a single DNA base pair results in a change in one of the 599 amino acids that make up the GAT-1 protein. The researchers found that the SLC6A1 gene is particularly sensitive to these missense variants, many of which can prevent GAT-1 from transporting GABA.

This study was a collaboration between a team at BioMarin Pharmaceutical Inc. and teams at the University of Oxford and the University of California San Francisco (UCSF).