Sunday syndrome #4: Concentrate!

This is another archival repost from the old blog — this time from Nov 2007.  The post is part four in a series. The series so far can be found here.

So far in the Sunday syndrome column, we’ve been talking in terms of the all-or-nothing loss (or gain) of a gene. This is biological development that we’re talking about, though. Development is an incredibly complicated process, and to understand why many syndromes occur, we have to understand a little more about just how complicated it is. Previously in the series, I’ve looked at gene-gene interaction, and gene-environment interaction, and begun introducing the idea that various elements cooperate to run developmental programs. This week’s element is quantity. Chemical concentrations, relative proportions of gene products, and other such measures, all contain data from the point of view of the developmental program. Syndromes may arise when a gene is deleted, even if there is an identical copy of the gene on the homologous chromosome. Other syndromes arise when there is an additional identical copy of a gene: the trisomies (extreme cases, where there is an extra copy of an entire chromosome), for example, cause Down’s, Edwards’, Patau’s and Klinefelter’s syndromes. In such cases, no gene has been entirely lost, and no novel genes have been introduced; the only difference is in quantities.

This week’s syndrome is Attention-Deficit Hyperactivity Disorder (ADHD).[1] ADHD is heritable: carrying certain gene variants predisposes one to ADHD. But none of those alleles has been shown to be either necessary or sufficient to explain the disorder. We are therefore looking at an issue with a developmental program, complete with its diverse collection of variable and non-variable influences. ADHD is, of course, characterised by a short attention span, and a disinclination to sitting still. This is the result of delayed neurological development: slow overall development means delayed or incomplete development of the controls that we put on impulsive behaviour. Because there are so many interacting influences, there are many subtle variations in the manifestation of ADHD, which in turn means that the cellular and molecular details of ADHD are difficult to determine. One thing that does appear to be relatively consistent, though, is the involvement of dopamine, a neurotransmitter that is known to influence many aspects of behaviour and cognitive activity. In ADHD, dopamine signalling tends to be reduced, but the situation is not as simple as saying that a particular gene has been lost. Common candidates for involvement in ADHD are dopamine transporters, which move dopamine across cell membranes; dopamine receptors, which mediate the cell’s responses to changes in dopamine levels; and enzymes which make chemical modifications to dopamine itself, thus altering its ability to interact with receptors and transporters. In some cases, the genes for these receptors, transporters, and enzymes may indeed be missing, but more commonly they carry a mutation which reduces their efficiency.

Take dopamine receptor D4 (DRD4), a gene which produces a protein whose job it is to sit in the membrane of neurons at synapses (places where two neurons communicate) and initiate activity inside the cell whenever it encounters dopamine outside of the cell. The internal activity of the cell will not amount to anything significant until the concentration of dopamine outside of the cell crosses a threshold: the continuous variation in dopamine concentration is translated into all-or-nothing effects. The most common allele of DRD4 includes a sequence of 48 base pairs which is repeated four times. Mutations are particularly common in repetitive sequences as “replication slippage” occurs when the DNA is duplicated during cell division; the daughter strand ends up with an incorrect number of repeats, which the copy-editing mechanism fails to correct. DRD4 alleles have therefore been observed with anything from two to eleven repeats of that 48 base pair sequence. The seven-repeat allele (DRD4 7R) is common enough for its association with ADHD to have been noticed. The additional copies of the repeating sequence in the DRD4 7R gene mean that the resulting protein has a slightly different structure, and has difficulty interacting with dopamine.[2] The result is that higher concentrations of dopamine are required to activate that activity inside of the cell: the DRD4 7R allele could be said to mimic dopamine deficiency in that situation. A similar variety of mutation in the dopamine transporter 1 (DAT1) gene — whose function is completely different from DRD4 — also reduces its efficiency, again mimicking dopamine deficiency.

Other types of mutation may have no affect on interactions with dopamine, but affect the lifespan of the gene product. Over time, all proteins accumulate damage, affecting their performance; the cell therefore has a system for clearing up old proteins. The products of some alleles, though efficient at their job, look to the cleaners like old wrecks, while others may be more susceptible to damage, and prematurely age. If production does not keep up with the cleanup operation, concentration will be lower than normal, and there will therefore be abnormal downstream effects. There are plenty of other examples, but the point is: there is more to molecular biology than gene sequences, and development is a web of variables. This is perhaps illustrated best by the suggestion that expression of dopamine receptor D2 (DRD2) is correlated with marital stability, and may mediate an effect of family environment on ADHD.[3]

That concentrations and proportions contain information would be a minor curiosity if it were restricted to a few specific examples, like dopamine in development of the nervous system. But cascades of concentration gradients and switches made of chemical proportions are the very stuff of development. Concentration gradients in the egg determine the body’s head-tail and front-back axis, and go on to set up further concentration gradients, which put cells onto a path of differentiation into their specialised jobs.[4] Other embryonic cells amplify random fluctuations in chemical proportions into the signals that tell organs where to develop.[5] Throwing such gradients and switches out of balance can be done with something far smaller than the loss of a gene, and have far greater implications than the loss of a gene in an insignificant system. We have approximately 25,000 genes: far fewer than the estimates, and a figure only widely accepted upon completion of the human genome project. The reason: genes are versatile and variable. That’s a theme I’ll return to in the next installment.


  1. ^ OMIM:#143465
  2. ^ Swanson JM, Flodman P, Kennedy J, et al. 2000. “Dopamine Genes and ADD.” Neurosci Biobehav Rev. 24(1):21–5
  3. ^ Waldman ID. 2007. Gene-environment interactions reexamined: Does mother’s marital stability interact with the dopamine receptor D2 gene in the etiology of childhood attention-deficit/hyperactivity disorder? Dev Psychopathol. 19(4):1117-28
  4. ^ See any introduction to development, e.g. Wolpert et al 2001. Particular favourite examples include the HOX genes and SSH/BMP in neurulation.
  5. ^ ibid. See e.g. Notch/Delta and Ephrins.

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