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
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The possibilities of science decoding century old disorders is pure magic. I know few of my friends whose kids have autistic kids and their lives have completely transformed after the diagnosis. I hope these research can provide relief to future parents and kids. Kudos to the all the researchers who are putting every piece of tiny information to discover the story of dysfunction. Thanks Rajini Rao for sharing all that info.
Thanks Rajini, no doubt this will all be unraveled eventually and things will get better!
Wow, Rajini Rao, when your post was referencing “we” at first I thought you were just taking a quote from the referenced article and then I read a bit more closely and followed the link. This is fantastic and fascinating. I guess I didn’t understand that this was the focus of your work. So very important, especially given the growing prevalence of these disorders.
Soon, we’ll be saying “I knew her when”….
Early intervention is key, Rama Drama . That is a whole area of study with more immediate consequences.
Hoping all part of the puzzle of our amazing brains comes together eventually, Christopher Fontes 🙂
Gideon Rosenblatt , this is only a small part of autism research 🙂 Our involvement in the topic comes from a long standing interest in these NHE proteins..we first discovered them in yeast. In plants they alter flower color and the acidity of grapes (wine, yay!). Only recently did we learn from geneticists that they are involved in neurological disorders. So that is what we focus on of late.
Rajini Rao The language delay is not really a characteristic of Autism, just appears on Kramer’s autism. In fact, it can be even the opposite in people with Asperger’s Syndrome.
PS. My first interaction with you was just after you returned from a conference about autism 🙂
Víktor Bautista i Roca , I remember it well. You corrected my faulty conference notes 🙂
Not sure how the variation in language breaks down in the spectrum. Interesting that it can be accelerated in Asperger’s.
Rajini Rao exciting research! Thanks for sharing.
Am I missing something here, Rajini? In this post you say:
“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
The Science Daily article states:
…”the team moved on to a third and more challenging step, in mouse brains. They homed in on astrocytes, a type of brain cell that clears the signaling molecule glutamate out of the way after it has performed its job.
Do glia and astrocytes both have this function?
John Condliffe, astrocytes are a type of glial cell.
Thanks, Steve Esterly . Hope that clarified your question, John.
It did, thanks.
Thank you very much for your post Rajini Rao
Perhaps the coming singularity will fix this. We (I) can hope. I was diagnosed with Asperger’s in 2008.
David Lazarus , Asperger’s are relatively lucky. I hope the diagnosis helped you and made sense. It’s tough on the little kids with severe communication deficits who are in their own private world that we cannot reach.
Very interesting & thank you for sharing a piece of your work Rajini Rao
Thanks, Cheryl Ann MacDonald 🙂
Thanks for sharing your research Rajini Rao !
Great work!
Morgan Catlin , who is this James that I am being compared to? 🙂
Beautiful research & post Rajini. I love hearing about your work! Thanks for sharing it with us.
Congrats on the publication Rajini! The research is very interesting; it is really a tour de force.
Congratulations on the Nature Com pub, Rajini Rao. I wonder if you can use PET and (4S)
4(3-[18F]Fluoropropyl)-l-glutamate ([18F]FSPG) to image differences in a transgenic mouse. Ideally the NHE9 knock-out mouse would have different [18F]FSPG levels that you could visualize in the PET image.Thank you Rajini Rao for another well written article, and congratulations on this excellent work. I appreciate that a scientist with a full schedule takes the time to share her work.
Thanks, all! It is my pleasure to bring some of our work to you 🙂
Chad Haney , there was a proton MRI done on one patient with a related mutation in NHE6. The authors say, “Single-voxel MRS of the brain was performed with a point-resolved spectroscopy sequence with chemical-shift water suppression (repetition time [TR] 1500 ms, echo time [TE] 30 ms). Volumes of interest were located in the left parietal white matter and in the right basal ganglia. The interpretation of the MRS study was limited because consent was only given for examination of a single patient and we were unable to use absolute metabolite concentrations. Nonetheless, it suggested increased levels of glutamate-glutamine complex in the basal ganglia”. Here is the image, what do you think?
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2427207/figure/fig3/
I’ll have a look later. Thanks
Very cool that something you were researching for other purposes turned out to have medical implications. Life as a scientist must be so fulfilling!
Thanks for sharing this accessible summary.
Jyoti Dahiya , that is a very perceptive observation! For a basic scientist, it is incredibly “exciting” and validating to receive a phone call from a clinician or geneticist telling us that what we have been studying for years because of its intrinsic scientific interest turns out to be a prime candidate for some devastating human disease. This happens over and over again and is proof that curiosity -driven research has huge dividends.
I agree Rajini Rao but we need to keep telling people that it takes years of basic research to make a small dent in applied science, e.g., clinical research. People need to be reminded that for-profit organizations only get involved at the end.
hi…
i am asperger/ADD/dyslexic
both my brother and step brother are the same but ADHD …
i am a medical doctor..
i am very interested to discover where and how we determine that something is a ‘disorder’ ….
i suspect that most things are so determined by their apparent suitability to ecology….
do u know of any other views .. and any way i might encounter them…
…
and thankyou for this post..it is interesting..
Thanks swati
Nice
Those are some excellent findings. The knowledge base just keeps growing and growing. It’s also a good example of how there might be complex answers in science. If we can figure out the autism switches, and then examine the related brain function changes like ADHD and anxiety or aggression for example, this will tell us so much.
Wow, I hope one day they do find cures on diseases. And an understanding of what makes a person get a certain disease or why they are prone to getting it. .. interesting post. 🙂
Rajini Rao being very interested in both biochemistry & psychology, i find, in autism research, a yawning gap in our understanding of the “middleware” between the two. in mild autism cases, for example, the behavioral effects are so complex that they go directly into the loci of personality, consciousness &, indeed, humanity.
nomad dimitri , you make a good point. If you search G+ for posts about autism, nearly all relate to people with mild personality differences, or Aspergers. The focus here is on acceptance and not a “cure”, with which I fully agree. Most scientific research however, is focused on classical autism where there is frequently no language, little or no communication with people and significant immune/digestive disorders. This makes sense because it is easiest to pin down a severe phenotype rather than a mild one, to begin to understand this complex disorder. Researchers show us tapes of kids who will not look in your eyes but may spend an hour examining a piece of lint. In contrast to the mild personality differences, severely affected autists need life long care and may never be able to hold a job. I heard from a parent who said that they could not leave home without diapering his son- he has constant diarrhea. The NHE9 mutations we study are typically accompanied by epilepsy. Now these are major issues that need to be investigated and treated at physiological and psychological levels.
Good points Rajini Rao . In addition to just the socialization issues present in “standard” Asperger’s and PPD-NOS type subjects, who do form a significant majority of those with the diagnosis, there tend to be significant co-morbidities of certain other conditions. Anecdotally, I hear from other parents who see a pairing of Asperger’s/aggression, or Asperger’s/anxiety/depression. There are obviously more variations than that, however it’s a common split. So all research into this is excellent. Not to mention how much it will inform us across other research lines about epigenetic effects on other and related conditions. I really think it is wonderful to live in an age approaching enlightenment as we can help achieve understanding and acceptance with knowledge.
The story in a soundbite: my short audio interview with NPR is here http://wypr.org/post/brain-talk-role-gene-nhe9-could-play-autism-0
can u say me what leads to an unwanted addiction?
Hi
To my god