Can genes explain brain disorders? Yes. Sometimes.
Over the past few weeks two articles have shown the promise and the difficulty of studying brain genes. One appears in the New England Journal of Medicine of May 20, and zeroes in magnificently on a gene for Tourette’s Syndrome.
That would be “a” gene, not “the” gene, since there isn’t and won’t be a single-gene explanation for this complex disorder. It begins in childhood, and can range from mild occasional tics to disabling stereotyped behaviors like throwing the arms and legs around in contorted movements. Vocal tics are part of the diagnosis, and these can take the form of repeated and involuntary yelling of socially prohibited utterances like curse-words or even racial epithets. Needless to say, all this has long interested people curious about how the brain produces language.
One curious thing about Tourette’s is that focused activity can abolish the tics. Oliver Sacks famously described a surgeon who had wild tics in department meetings (he had to sit on the floor in a corner to avoid hurting himself and others) but had an absolutely steady hand in the operating theater. Another oddity is the recent proposal, by my colleague at Emory Shlomit Ritz Finkelstein, that the involuntary utterances may be different in different cultures; as long as they give offense in a given social surround, they’ll apparently do the job that the Tourette’s brain is seeking.
We’ve known for decades that the problem involves a circuit from cerebral cortex to basal ganglia to thalamus and back to cortex, possibly also involving the limbic system and frontal lobes, and that part of the circuit uses the neurotransmitter dopamine, because drugs that block dopamine help. But the new research reveals something else entirely.
A team based at Yale found a family in which the father and all eight of his children, but not their mother, have Tourette’s. This had to be the signature of simple Mendelian inheritance of a single gene, most likely a dominant gene on a non-sex chromosome. The chances were still very low that all eight kids would have it, but they did.
In the gene-sequencing, a small segment of chromosome 15 was flagged and studied more closely, and the team narrowed in on the gene for an enzyme called histidine decarboxylase (HDC). This is the rate-limiting enzyme in the brain’s manufacture of another neurotransmitter, histamine.
More zeroing in put the finger on the 951st DNA base in the coding part of the gene. Here a simple, single-base mutation substituted an A (adenine) for a G (guanine). The father and every affected child had the substitution. The mother and her unaffected blood relatives did not.
This is gorgeous. This is high school genetics, or maybe today middle school, not to do but to understand. So simple; so elegant; so revealing.
More sleuthing: the team studied the proteins made by the normal and abnormal genes. The result of the base substitution was a premature stop signal that dwarfed the protein from a normal length of 662 amino acids to a mere 316. This abnormal protein was the dominant gene product that prevented normal histamine production in the patients’ brains.
Not only that, but lab studies had shown that neurons projecting from the rear end of the hypothalamus, using histamine, end on the circuit already implicated in Tourette’s. And finally, experiments show that mice deficient in HDC, and therefore in histamine, have stereotyped rearing, sniffing, and biting–thought to be a plausible model for human tics.
Now, it’s true that this family represents only a teensy fraction of people affected by Tourette’s, and few other cases will fit this model. So why am I so excited?
It’s not just the elegance of the science, although I love that. It’s that there are already drugs under study in humans that specifically stimulate histamine receptors of they type that are now implicated in Tourette’s. This study may bring a new treatment closer.
So where’s the down side? Well, it’s not in this line of work, but in another study, showing the disappointment so common in genetic studies.
A group studying identical twins discordant for multiple sclerosis—one twin has MS, the other doesn’t, and they’re past the age when it would have appeared if both were going to get it—published their results in Nature on April 29th. The cover dramatically showed the silhouettes of a woman in a wheelchair and another woman standing beside her. But the research report inside showed…nothing.
MS disables people by stripping their neurons of myelin, the fatty sheath that makes axon cables work well. The idea was that completely sequencing the genomes of the twins might show mutations that one had suffered but the other had not. If it had, the team could have gone on to do what the Tourette’s team did, perhaps pinpointing a new clue to future treatments.
No such luck. Very thorough study showed no genetic differences, and less thorough backup studies of two other discordant twin pairs likewise came up empty-handed.
It’s still interesting, because it means that in such cases some environmental causes were responsible, not genes. But we already knew that unknown environmental factors play a role in MS, and this research gives no further clues to what they are.
So you win some, you lose some. But both these strategies for finding genetic needles in haystacks are very valid, and there will be more good news from this kind of research.