Our brains are complicated structures in a delicate balance, and there are many ways that their function can go wrong. Tourette's Syndrome, for instance, is a strange disorder where the afflicted have motor and vocal tics of varying severity—the most dramatic cases have socially debilitating outbursts of grunting, barking, or shouting, but most cases involve only minor twitches. They are driven by unusual behavioral compulsions beyond their control (I think many of our behaviors are driven by deep biological imperatives that we take for granted and don't notice because everyone else is doing the same thing…Tourette's is a situation where the drives generate behaviors that do stand out). A new paper in Science describes one gene that may play a role in Tourette's, and I thought the most interesting thing about it was the multiple, subtle ways the gene can be modified to affect the behavior.

The gene of interest is SLITRK1. This gene gets its name from its similarity to Slit, a well-known gene that is secreted and can repel growing neurons, and Trk, a family of tyrosine protein kinase receptors—it's a protein that can bind extracellular signaling molecules, and can also affect the growth of neuronal processes. SLITRK1 is also expressed in specific regions of the brain that are known to be affected in Tourette's Syndrome. That's a suggestive combination.

Just being suggestive isn't enough, though: you need to find evidence of a link. Here's an example of such evidence, a teenaged boy with an easily detected chromosomal change.

Mapping of a de novo chromosome 13 paracentric inversion in a child with TS. (A) Pedigree of Family 1, with a single affected male child with TS and ADHD (16). The parents, grandparents, and younger sibling are not affected with TS, ti cs, ADHD, TTM, or OCD. Four maternal siblings, not presented on the pedigree, are all unaffected. (B) G-banded metaphase chromosomes 13. The ideogram for the normal (left) and inverted (right) chromosomes are presented.

The pedigree shows that the affected individual (the dark square) has no family history of Tourette's Syndrome; he's a brand new case, likely the product of a novel mutation. Examining his chromosomes revealed a change in chromosome 13, with a region (q11 to q33) inverted, which was not shared with any of his other family members. There are 3 genes in this region that might be affected, but only SLITRK1 has the association with the brain to make it a likely candidate.

This boy has a perfectly normal SLITRK1 gene, though. It's within the inverted region, but has not been damaged in any way by the flip—it has only changed its position within the chromosome. The investigators suspect a position effect. Gene activity can be modulated by the location within a chromosome, by the level of activity of neighboring genes. For instance, cellular mechanisms to inactivate genes, such as methylation or the binding of proteins, are not perfectly precise, so a gene that is located near a region that is strongly inactivated is at risk that it will be 'accidentally' silenced with a high frequency. They suspect that this boy's SLITRK1 gene has been downregulated in its new location.

With SLITRK1 as a new suspect as one causal agent in Tourette's Syndrome, the investigators began screening known Tourette's sufferers for more anomalies in this particular gene. Most were negative. This is not a surprise; complex behavioral syndromes are not going to be easily pinned down to precisely one cause. However, they did find another individual with the pedigree to the right; he was affected with Tourette's, and his mother (the half-shaded circle) had a related syndrome, trichotillomania.

When their SLITRK1 genes were screened, mother and son were found to have something unique, that was not shared with other, unaffected members of the family. Their gene had a truncating frameshift mutation. This is not a subtle change at all, but an abrupt break in the gene product. One of their copies of the SLITRK1 gene is completely nonfunctional.

Identification of a truncating frameshift mutation in SLITRK1. Diagram of the normal and predicted mutant SLITRK1 protein.

They found other cases of a changed SLITRK1 gene in individuals with Tourette's, but this one is the most subtle of them all. In this case, the coding sequence of the gene is unchanged, but one nucleotide of the untranslated region of the gene is changed from a G to an A. This a portion of the DNA that gets transcribed into the RNA string, but is clipped out of the sequence that will make the actual protein—you'd think it wasn't particularly significant. In this case, however, the change helps the SLITRK1 RNA bind better with a specific micro-RNA, miR-189. Micro RNAs are tiny pieces of RNA that bind to transcripts and modulate their translation into protein, in this case to reduce the production of SLITRK1 in the cells.

So, in a minority of Tourette's cases, they've discovered three kinds of changes to SLITRK1 that are correlated with the syndrome: a change in gene position within the chromosome, a truncation of the gene product, and an increased sensitivity to micro RNA binding. What exactly does SLITRK1 do to neurons?

You can't poke around in Tourette's brains, and you can't go around tweaking their genes to see what happens either, but you can do a cool experiment: introduce human SLITRK1 genes into mouse cells.

SLITRK1 over-expression enhances dendritic growth in cortical neurons. Images of cell bodies and dendrites, as well as proximal axonal segments (a), of representative GFP-immunopositive cortical neurons cultured for 6 DIV. Primary cultures were prepared from embryonic day 15.5 (E15.5) embryos that were electroporated in utero at E14.5 with control GFP plasmid (GFP), GFP and wild-type human SLITRK1 (GFP + wt SLITRK1), or GFP and human SLITRK1 carrying the frameshift mutation (GFP + mut SLITRK1).

On the left are a quartet of mouse neurons in the control group at 6 days in vitro. They had a construct introduce that consisted of only GFP, green fluorescent protein, as a marker.

In the middle are a quartet of neurons containg GFP and human wildtype SLITRK1. These were significantly bushier than the controls.

On the right are mouse cells with the truncated mutant form of SLITRK1; they are significantly less branchy than the cells with wildtype SLITRK1. The presence of the gene is clearly associated with more complex arbors in these cells.

So changes in this gene are associated with changes in behavior, and gene expression affects growth and morphology of neurons. I'm comfortable with the case made that this gene affects processes that are responsible for some cases of Tourette's Syndrome. I want to emphasize, though, that this is not a Tourette's Syndrome gene—it is one among many genes that modulate complex interactions in brain development, and contributes to the molecular machinery that assembles the brain. We have to be very careful about statements that a particular gene is for something. We wouldn't say that cadmium red pigments are responsible for an artist's painting of a sunset, after all, even if they are helpful in generating brilliant color. A good artist can make a great painting with only ochre in his spectrum of reds, and all the cadmiums and chromiums in the world won't turn a duffer at the easel into a Matisse. It's the same with genes like this that affect the brain; a broken SLITRK1 does not make for a broken brain, just as an unmutated form doesn't guarantee a healthy one—it just means the individual is working with a different palette.

Abelson JF, Kwan KY, O'roak BJ, Baek DY, Stillman AA, Morgan TM, Mathews CA, Pauls DL, Rasin MR, Gunel M, Davis NR, Ercan-Sencicek AG, Guez DH, Spertus JA, Leckman JF, Dure LS 4th, Kurlan R, Singer HS, Gilbert DL, Farhi A, Louvi A, Lifton RP, Sestan N, State MW (2005) Sequence Variants in SLITRK1 Are Associated with Tourette's Syndrome. Science 310(5746):317-20.