Monday, November 8, 2010

Autism-Related Gene Spotlight: SLC4A10

EXECUTIVE SUMMARY: SLC4A10 is a member of a large family of genes that encode proteins for transporting ions (charged particles) across cell membranes. Within that (super)family, SLC4A10 belongs to a family of transporter proteins specializing in bicarbonate (HCO3-) ion transport, which is important for maintaining a constant pH within the cell --- i.e., preventing it from becoming too acidic or basic for the cell's biological machinery to function. SLC4A10 encodes a version of this transporter protein specific to certain cells of the central nervous system, and mutations disrupting this gene have been found in two instances: first, in a set of autistic twins who participated in a genomic study, and second, in a girl with epilepsy and intellectual disability. Disruption of this gene is thought to make brain cells more excitable, which can lead to seizures (which is probably why the girl in the second case study has them).

Where is it?
Its "cytogenetic band" is given as 2q23-q24 (or, alternatively, 2q24.2), which means that it's on the long arm ("q" as opposed to "p") of chromosome 2, somewhere in the middle.

Here's a map of chromosome 2, with a red line marking where SLC4A10 is:
This gene spans 360,942 base pairs (which is fairly large, but not enormous; there's a lot of variability in gene size, with the smallest ones only a few hundred bases long and the largest spanning several million bases --- see this e-textbook chapter for details), covering the distance between bases 162,480,845 and 162,841,786 (measuring from the centromere to the end of the chromosome).

What does it do?
The name SLC4A10 refers to its membership in a family of genes encoding similar proteins: solute carrier family (SLC) 4, which is a group of ten genes whose protein products transport bicarbonate ions (HCO3-) across cell membranes.

Bicarbonate ion (and its protonated form, carbonic acid, which is readily synthesized from carbon dioxide and hydrogen ions) plays a central role in regulating pH, both within cells and outside of them, as in blood. pH is a measure of acidity, expressed as the (negative) logarithm of the concentration of hydrogen ions (H+) in the fluid being tested. Pure water has a "neutral" pH of 7 (meaning that, of the H2O molecules making up liquid water, an approximately equal number exist in their dissociated forms of H+ and -OH at any given time --- if an acidic or basic compound is added, it will either add or remove H+ to the solution, and thus move the pH down or up); the water inside human bodies is slightly basic and has a pH of around 7.4 ("physiological pH"). Bicarbonate/carbon dioxide can act as a "buffer" between an acidic or basic substance and the physiological environment: depending on what form it's in, it can either donate (H2CO3 --> HCO3- --> CO32-) or receive (CO32- --> HCO3- --> H2CO3) hydrogen ions and keep the surrounding fluid from having to disrupt its acid-base equilibrium.

Because bicarbonate cannot diffuse across cell membranes by itself, it needs to be transported into cells by ion-exchanging membrane proteins whenever it is needed. The protein produced by SLC4A10 ferries bicarbonate ion and sodium ion into the cell while expelling a chloride ion from the cell. Two bicarbonate ions are imported for every sodium ion, which keeps the net gain/loss of electrical charge at zero.

This particular gene is primarily expressed in the central nervous system (i.e., the brain and spinal cord), though related genes encode similar bicarbonate-transporting proteins for other tissue types. In mice, SLC4A10 is expressed in some types of brain tissue but not in others: it was specific to gray matter (neurons, but not glial cells), and was not expressed in white matter; and it was also specific to certain regions of the brain: the olfactory bulb, cortex, hippocampus and cerebellum.

In neurons, ion concentrations inside and outside the cell play a role in whether a given neuron will "fire" --- undergo dramatic and rapid change in the electrical potential difference across its membrane, which triggers electrical and/or chemical signaling of adjacent neurons --- so ion transporters in neurons also help mediate neurotransmission.

What mutant versions of this gene have been discovered?
In the article I mentioned in my last post --- Sebat et al., 2007 (full text here) --- the authors report finding a spontaneous deletion of the first coding region of SLC4A10 in a pair of twin girls with autism.

There is also a recent report of a girl with epilepsy and intellectual disability having part of this gene --- a 48,000-base stretch of the 2q24 region falling between coding regions 2 and 3 of SLC4A10 --- moved to another chromosome: chromosome 13.

How do these mutations affect protein function?
Mice bred with the entire SLC4A10 gene missing were found to have much smaller brain ventricles than normal mice, and also had altered choroid plexus tissue. (The choroid plexus is where cerebrospinal fluid is made and waste is filtered out of it; active-transport proteins are especially dense there). Researchers found it harder to induce seizures in these mice as compared with normal mice using the proconvulsant (i.e., seizure-inducing) drugs pentylenetetrazole and pilocarpine.

Neither of the mutations observed in humans involves knocking out the entire gene; one involves deleting the first (of twenty-six) coding region, and the other involves switching a fairly long non-coding region with a sequence from another chromosome. Nothing is deleted in that case, but the insertion of something random into the middle of a gene might derail the process of assembling a working protein using that gene's (garbled) instructions. So both mutations impair the production of this protein to an unknown degree --- the protein probably isn't completely absent, but it might be present in reduced quantities or truncated, less-than-fully-functional form.
How common are they?
Very rare. Mutations in this gene are probably only a factor for a tiny, tiny minority of autistic people, whom I would suspect also have seizures.

Database entries for this gene: AutDB, Entrez Gene, Ensembl, Genatlas, GeneCards, SFARI Gene
Damkier, H., Aalkjaer, C., & Praetorius, J. (2010). Na+-dependent HCOFormula Import by the slc4a10 Gene Product Involves Cl- Export Journal of Biological Chemistry, 285 (35), 26998-27007 DOI: 10.1074/jbc.M110.108712

Gurnett CA, Veile R, Zempel J, Blackburn L, Lovett M, & Bowcock A (2008). Disruption of sodium bicarbonate transporter SLC4A10 in a patient with complex partial epilepsy and mental retardation. Archives of neurology, 65 (4), 550-553 PMID: 18413482

Jacobs, S., Ruusuvuori, E., Sipila, S., Haapanen, A., Damkier, H., Kurth, I., Hentschke, M., Schweizer, M., Rudhard, Y., Laatikainen, L., Tyynela, J., Praetorius, J., Voipio, J., & Hubner, C. (2008). Mice with targeted Slc4a10 gene disruption have small brain ventricles and show reduced neuronal excitability Proceedings of the National Academy of Sciences, 105 (1), 311-316 DOI: 10.1073/pnas.0705487105

Sebat, J., Lakshmi, B., Malhotra, D., Troge, J., Lese-Martin, C., Walsh, T., Yamrom, B., Yoon, S., Krasnitz, A., Kendall, J., Leotta, A., Pai, D., Zhang, R., Lee, Y., Hicks, J., Spence, S., Lee, A., Puura, K., Lehtimaki, T., Ledbetter, D., Gregersen, P., Bregman, J., Sutcliffe, J., Jobanputra, V., Chung, W., Warburton, D., King, M., Skuse, D., Geschwind, D., Gilliam, T., Ye, K., & Wigler, M. (2007). Strong Association of De Novo Copy Number Mutations with Autism Science, 316 (5823), 445-449 DOI: 10.1126/science.1138659

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