A Part of the Puzzle: NHE9 and Autism
❑ People with autism have difficulty with social interaction, language delay and stereotyped interests or repetitive behaviors that vary widely in severity between individuals. Currently diagnosed at rates of 1 in 88 children, autism spectrum disorders are an urgent public health issue.
❑ Autism is one of the most inheritable of neurodevelopmental disorders. We know this from twin studies, family trees and rare chromosomal abnormalities. But it is also the most complex – because no single gene contributes to more than 1% of autism cases. We describe this as extremely heterogenic. Most likely, these myriad genes impact a few common pathways, such as signaling between nerve cells. Although geneticists trawl through massive banks of DNA sequence and clinical data to uncover candidate genes, each one still has to be analyzed individually to separate the chaff from the grain- harmless variations in DNA (polymorphisms) from disease-causing mutations.
❑ In a study just published we focused on a gene that had been flagged as a suspect in attention-deficit hyperactivity disorder, addiction and epilepsy as well as autism spectrum disorders. 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.
❑ We drew upon decades of basic research in simpler models like bacteria and yeast to develop a structure of the transporter protein (inset in the image). 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 mutations to find those that resulted in 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, that could be a target for future therapy.
News Flash: Today’s Nobel prize announcement in Physiology and Medicine celebrates three scientists who contributed to our understanding of cellular trafficking: Randy Schekman (Berkeley), Jim Rothman (Yale) and Tom Sudhof (Stanford). More: http://www.nobelprize.org/
Our News Story: http://www.sciencedaily.com/releases/2013/09/130930114101.htm
REF: Kalyan C. Kondapalli, Anniesha Hack, Maya Schushan, Meytal Landau, Nir Ben-Tal, Rajini Rao. Functional evaluation of autism-associated mutations in NHE9. Nature Communications, 2013; 4 DOI: 10.1038/ncomms3510