Gene mutation in the brain of autism patients alters behaviors in mice

Autism spectrum disorder (ASD) has a wide range of possible causes, including genetics and environmental factors. Now, a new study suggests that a brain protein mutation may shed light on the mechanism of neurological and developmental illness.

A team of researchers at the University of Alabama at Birmingham found that a brain protein mutation in patients with autism, when placed in the brains of mouse models, has caused severe alterations of behaviors that bear a resemblance to those seen in humans with autism spectrum disorder (ASD).

Autism spectrum disorder (ASD) or commonly known as autism affects 1 in 160 children across the globe. The neurological disorder typically begins in childhood and tend to persist until adolescence and adulthood. In the United States, about 1 in 59 children has autism spectrum disorder (ASD) and it’s about four times more common among boys than in girls.

ASD tends to occur more frequently in people with genetic or chromosomal conditions. In fact, about 10 percent of children with autism have other disorders, including fragile X syndrome, Down syndrome, tuberous sclerosis, among others. ASD may run in families and in children born to older parents.

Image Credit: Africa Studio / Shutterstock
Image Credit: Africa Studio / Shutterstock

Possibility of a potential mechanistic underpinning

In the study published in The Journal of Clinical Investigation, the researchers found that a de novo gene mutation that encodes a brain protein, known as dopamine transporter (DAT),  in a child with autism when placed in the brains of laboratory mice, caused severe alterations in behaviors that mimic those seen in people with ASD.

The researchers believe that their findings show a ‘possibility of a potential mechanistic underpinning’ in some patients for some of the behaviors commonly seen in children with ASD and in those with attention deficit hyperactivity disorder (ADHD).

Brain neurons release dopamine, a brain neurotransmitter, from the axon ends. From there, dopamine crosses the synapse between the axon and a neighboring neuron, stimulating a response in the neuron receiving the neurotransmitter. The dopamine transporter is found in the transmitting neuron’s membrane and it works by performing dopamine reuptake. It pumps released dopamine back into the transmitting neuron, hence, stopping the receiving neuron’s response.

The dopamine system (DA) is important in the regulation of motivation, attention, activity, and reward processing. Dopamine plays a pivotal role in many brain functions and it’s no surprise that any alteration in the dopamine system has been linked to various neuropsychiatric disorders, including Parkinson’s disease, bipolar disorder, substance use disorder, attention deficit hyperactivity disorder (ADHD), and autism spectrum disorder (ASD).

ASD is a neurological and developmental disorder that impairs one’s social communication and interaction with patterns of restricted or repetitive behaviors, activities, and interests. In some previous studies, they found that some features or characteristics of ASD patients may be associated with abnormal dopamine system (DA) signaling.

Gene mutation for human DAT produced abnormal behaviors in mice

To study whether the brain protein mutation is responsible for distinct behaviors manifested by ASD patients, the researchers analyzed a mutation in the gene for human DAT found in a child with ASD. The gene mutation creates a substitution at amino acid 356 of DAT, changing threonine to methionine, making the gene mutation DAT T356M.

They tested the brain protein mutation in laboratory mice. They observed that the mice with two copies of DAT T356M gene mutation exhibited severe alterations in behavior resembling that of humans with ASD. On the contrary, mice with just one copy of the mutation showed no changes.

Some of the behaviors observed include decreased marble burying and loss of social dominance. Marble burying is an innate behavior of laboratory mice that is a result of their desire to investigate. Mice with the brain protein mutation manifested repetitive rearing and learning of how to balance on a rotating rod. These behaviors show repetitive behaviors, a common manifestation of ASD in humans.

Aside from repetitive behaviors, mice with the mutation exhibited hyperactivity based on an increased spontaneous locomotor activity.

“Given the number of roles of DA in behavioral learning, reward processing, and action selection, this work presents the exciting possibility of a potential mechanistic underpinning (in at least a subset of patients) for the altered behaviors observed in ASD and ADHD,” the authors wrote in the study.

“Future work should seek to determine to what degree DA dysfunction exists across patients with these neuropsychiatric disorders and whether striatal dysfunction plays a central role in the pathology of these conditions,” they added.

Journal reference:

DiCarlo, G., Guilar, J., Matthies, H., Harrison, F., Bundschuh, K., West, A., Hashemi, P., Herborg, F., Rickhag, M., Chen, H., Gether, U., Wallace, M., and Galli, A. (2019). Autism-linked dopamine transporter mutation alters striatal dopamine neurotransmission and dopamine-dependent behaviors. The Journal of Clinical Investigation.

Angela Betsaida B. Laguipo

Written by

Angela Betsaida B. Laguipo

Angela is a nurse by profession and a writer by heart. She graduated with honors (Cum Laude) for her Bachelor of Nursing degree at the University of Baguio, Philippines. She is currently completing her Master's Degree where she specialized in Maternal and Child Nursing and worked as a clinical instructor and educator in the School of Nursing at the University of Baguio.


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