From left James Sutcliffe, Ph.D., Ryan Delahanty, Ph.D., Robert Macdonald, M.D., Ph.D., and Jingqiong "Katty" Kang M.D., Ph.D. (photo by Joe Howell)
Genetic variant linked to autism
The list of genes that increase risk for autism has a new entry.
Researchers at Vanderbilt University Medical Center have identified a genetic variant — a change in the DNA code — that affects the function of a neurotransmitter receptor and is associated with autism, specifically when the variant comes from the mother.
The findings, reported in the journal Molecular Psychiatry, are the first to link a specific genetic change in a GABAA receptor to the disorder, said James Sutcliffe, Ph.D., associate professor of Molecular Physiology & Biophysics and one of the lead investigators. They could provide a rationale for GABAA receptor-directed therapies for patients with this particular change.
Autism spectrum disorders are characterized by impaired verbal communication and social interaction, and by restricted and repetitive patterns of interest or behavior. They can range from relatively mild to quite severe and affect as many as one in 150 children in the United States, about three-quarters of them boys.
Evidence from twin and family studies has demonstrated that autism has a strong genetic component. One of the most common chromosomal changes associated with autism is duplication of a region of chromosome 15, inherited from the mother. Genes within this region — including the gene for the GABAA receptor b3 subunit (called GABRB3) — are suspected to play a role in autism.
Variation in the GABRB3 gene also has been associated with epilepsy, a condition known to affect some individuals with autism.
With collaborators in Chicago, Sutcliffe and Ryan Delahanty, Ph.D., screened for variation in the GABRB3 gene in 100 patients with autism and found a single change, which altered one amino acid in the protein.
They then examined this variant in more than 1,000 families that have at least one member with autism and identified 17 families with the variant.
“Interestingly, when transmitted from the mother, this variant causes significant risk for autism, but not when transmitted from the father,” Sutcliffe said.
The finding — and the maternally transmitted chromosomal duplications — support the notion that genes from this region are expressed in a way that depends on the parent-of-origin, a phenomenon known as imprinting.
To explore the functional effects of the DNA change in the GABRB3 gene, Robert Macdonald, M.D., Ph.D., professor and chair of Neurology and Jingqiong Kang, M.D., Ph.D., research assistant professor of Neurology, studied the mutant receptor in cultured cells.
They found that the DNA change negatively impacts the processing of the GABAA receptor protein in the cell so that less GABAA receptor protein reaches the cell surface.
The outcome is diminished GABAA receptor function in cells that have the gene mutation.
Because GABA receptors switch roles as the brain matures — they are excitatory (increase neuronal firing) in the developing brain and then inhibitory in the mature brain — understanding how the reduced GABAA receptor function contributes to autism is complicated.
The investigators plan to develop a mouse model with the GABRB3 mutation in order to study its role in brain development and neuronal signaling.
“At this time, we understand that the genetic etiology of autism is highly heterogeneous, with existing data showing a combination of rare genetic variants that confer significant individual risk and common variants that add only modestly to susceptibility,” Sutcliffe said. “We hope that as more such risk factors are identified, we'll have a better handle on the underlying genes and pathways that are dysregulated.”
Families in the study were recruited at Vanderbilt University, the University of Chicago and the University of California at San Diego, or they were obtained from the National Institute of Mental Health Repository. The National Institutes of Health supported the research.