Autism is currently being diagnosed at staggeringly high numbers of 1 in 88 children in the US (1 in 50, for boys), emerging as a major public health concern. Individuals can show a wide range of severity along the autistic spectrum, which is characterized by impaired language and social communication, stereotyped interests and repetitive behavior. Research has revealed a strong genetic component to autism, with many candidate genes identified by trawling through massive banks of genetic and health data from thousands of patients. Despite this clear genetic link, however, pinpointing autism-causing variants is a huge challenge. This is because no single gene or mutation contributes to more than 1% of autism cases. Most likely, these myriad genes impact a few common pathways, notably, signaling between nerve cells. Each candidate gene has to be evaluated individually before we can distinguish harmless variations in DNA (polymorphisms) from the more serious mutations that cause the disorder.
In a study just published we focused on a gene that had been flagged as a suspect in autism, as well as some other neurological disorders such as attention-deficit hyperactivity disorder, addiction and epilepsy. We knew that the gene made a transporter named NHE9 that shuttled positively charged particles of hydrogen, sodium and potassium into and out of cellular compartments called endosomes. By regulating the acidity inside these compartments, we showed that NHE9 controlled traffic to the cell surface and delivery of cargo (such as the neurotransmitter glutamate) critical for communication between nerve cells. One potential therapeutic approach would be to use drugs that make the endosomal pH more alkaline, to counter the effect of increased acidity from NHE9 mutations.
We drew upon decades of basic research in simpler models like bacteria and yeast to develop a structure of the transporter protein. To do this, we used evolutionary conservation analysis to predict if variants would be harmless or disruptive of the protein structure and function (simply, highly conserved portions of the protein are critical for function, whereas the more variable regions are often not). Using yeast as a model, we quickly (and cheaply!) screened through patient variants to show that they caused a loss of transport function. Then we extended our findings to the more complex neurobiological model: glial cells from mouse brains. We chose to study these cells because they are critical for mopping up neurotransmitter glutamate from nerve junctions, and we knew that patient brains showed elevations of glutamate, which tend to spark seizures. We hope this systematic screening process will be useful in the near future when gene sequences are routinely available for everyone, so we can determine risk levels in patients. Also, our study sheds a spotlight on the importance of trafficking in neurological disorders, revealing possible targets for future therapy.
Rajini Rao is Professor of Physiology at the Institute for Basic Biomedical Research of the Johns Hopkins University. Her research specialty is to understand how transport of ions across cell membranes relates to human health and disease. She has 30 years of experience investigating ion transporters that include proton pumps, calcium pumps and sodium-proton exchange proteins. Her laboratory was the first to discover the endosomal Na+/H+ exchangers (eNHE) and recognize them as distinct from those at the plasma membrane. These transporters have now been implicated in a range of neurological disorders including autism, attention deficit hyperactivity disorder, epilepsy, mental disability and Christianson’s syndrome. Currently, Dr. Rao combines the use of yeast and neurobiological models to determine how mutations in eNHE lead to neurological disease.
Her academic activities are divided between education, mentoring and research. As the Director of the Graduate Program in Cellular & Molecular Medicine, she oversees a multi-departmental training program with a focus on translational research that includes approximately 130 faculty mentors and 150 graduate students (Ph.D., M.D./Ph.D. and D.V.M/Ph.D.). She is also a faculty mentor in other graduate programs at the School of Medicine (Biochemistry, Cell & Molecular Biology, and Cellular & Molecular Physiology) where she teaches graduate and medical students. Dr. Rao plays an active role in advocating for women and minority groups in academia. She chairs the Committee on Professional Opportunities for Women at the Biophysical Society, where she has assumed multiple leadership roles.
Learn more about Dr. Rao
Read Researchers Ferret Out Function Of Autism Gene | Johns Hopkins Press Release
Johns Hopkins Adult Autism and Developmental Disorders Center
The Adult Autism and Developmental Disorders Center provides comprehensive mental health services for adults with any of a wide range of developmental disorders, including Autism and Asperger’s, fetal alcohol exposure, genetic disorders (such as Down’s, Fragile X, and others), cerebral palsy, and various intellectual disabilities.
Wendy Klag Center for Autism & Developmental Disabilities
The Center unifies and expands current research and education efforts at the Johns Hopkins Bloomberg School of Public Heatlh. It will encompass a broader array of research and educational goals across the fields of public health including not only epidemiology, but also health services research, developmental research, policy research, population and family dynamics and beyond.