Friday, May 15, 2009

Even single-gene disorders are complex

We've written a lot about complex disease in this blog, but we thought it was now time to give the complexity of single-gene disorders its due. Genes for what are often called 'simple' Mendelian traits (traits that are inherited in families in predictable patterns) are much easier to find than genes for complex traits like heart disease or asthma, but that doesn't make them simple.

In part, it's easier to define a 'simple' trait--for example, some forms of oligodontia, or missing teeth, run in families and most forms are due to mutations in Msx1 or Pax9. But it turns out that even a trait that should be easy to define isn't so straightforward--when multiple family members are affected they aren't always missing the same teeth, or the same number of teeth. So, there's something about the timing of the initiation of teeth during development that varies, and probably not by much, but enough to make the phenotype unpredictable, and the variation may well be random.

And, of course more complex phenotypes are even more unpredictable, even if due to single genes. A rare genetic disorder called hypokalemic periodic paralysis (hkpp) is one such trait. This is a channelopathy, an ion channel disorder, usually of sodium ion channels, which regulate the flow of ions into and out of the cell, but in individuals with hkpp, they let potassium into muscle cells but don't let it out in a timely way, thus weakening or paralyzing the muscle.

Hkpp involves anything from fleeting weakness to full paralysis, and in rare cases can be fatal if breathing is involved. The attacks generally resolve within hours, or sooner if the individual consumes potassium, but sometimes can linger for weeks. There are known 'triggers', including heat, hunger, sugar, carbohydrates, alcohol, exercise, and rest after exercise, but attacks can happen even without a trigger, and not everyone shares all the same triggers. So, in a sense this would seem to be a classic case of gene by environment interaction--sometimes. Why is there no apparent trigger for some attacks? And, it's interesting that age of onset is typically during adolescence--so why were these channels seemingly doing their job properly during the active childhood years?

Causative mutations have been found in at least three genes, and have been traced in families, but 30% of the families with this disorder don't have mutations in these genes (and often don't share the classic food triggers), and individuals with the same mutation within an affected family can have very different forms of the disorder, from no symptoms at all to just one in their lives to daily episodes of full paralysis.

A similar description could be written for most 'simple' single-gene disorders. The more common the trait, or the more intensely it has been studied, the more this has been shown. Usually, the story is different in different populations, and this is what would be expected on grounds of evolution (population history): in each region of the world, different mutations have arisen or risen in frequency, there are different environmental exposures, and the genomic background (variation at genes other than the 'causal' gene) differs, even with similar phenotypes.

The classic examples are diseases like PKU, cystic fibrosis, and even genes related to resistance to malaria (like sickle-cell hemoglobin). Even the once-simple ABO blood group system is like this. So, if simple diseases are so complex, it's no wonder that complex diseases are so hard to understand.


Anonymous said...

i'm going off tangent here, and i don't mean no disrespect to those suffering.

just like the Earth is just but an atom in the scale of the Universe, and still can be a complex entity with the humans and oceans and mountains. complex is really something relative eh?

and i think that's what makes things all the more, intruiging and frustrating and interesting at the same time. and i thank you both for this blog, sharing what's being discovered and thoughts to even common people like me. =)

Anne Buchanan said...

Thank you for your appreciation and your thoughts. Indeed, complex is relative.

A problem in human genetics has been that researchers have assumed that the lessons of 'simple' disease (that causative genes can be found for any disease) can be applied to all diseases, but it looks like this isn't so, as we've tried to explain. So, our use of the word 'complex' in this context has the particular meaning of diseases that seem to be caused by multiple genes, or by genes interacting with some aspect of the environment, or even of single-gene diseases caused by different genes in different families.

The more we look, the more complex it appears.

Anonymous said...

a Mandelbrot set if you may?

and even this have not taken the Environmental interactions into consideration.

Anne Buchanan said...

Yes, true, most things turn out to be complex, even when not every causative or interacting factor is considered. The problem is that, in medicine, the aim is to predict or prevent disease, or at least to explain risk. No one likes to hear that that can't be done. The same is true in evolution--no one likes to have a trait whose origin we can't explain. And, in both cases, when do we know enough that, even when we don't know all the details, we can be fairly certain we have an explanation of the main effects?