Saturday, October 23, 2010

A genetic origin of the demon itch

One problem with writing a blog is that you write each post separately. It's hard to keep a grand plan in mind and so, even if you think you're focused enough (e.g. eczema research and what it's like to live day-to-day with the condition) you keep getting buffeted around by the news of the day. Such as that PLoS ONE report I wrote about on Thursday.

Hidden B tells me I ought to follow up on some of the promises I made earlier on-- such as to look more deeply at filaggrin and heritability-- and that this would make for a less disjointed read. What Hidden B wants, Hidden B gets.

Two journals in particular have begun to emerge for me as great sources of information about genetics, allergy, and eczema research. There's the Journal of Allergy and Clinical Immunology, of which Donald Leung is the editor. Leung is the scientist leading the Atopic Dermatitis Research Network, funded by $32M from the NIH. So it's no surprise that his journal publishes some good, relevant research. I've read a few papers from the journal and have been impressed by the quality of the work and the writing-- and, believe me, you can't say this about every journal.

Look up "filaggrin" in Wikipedia. The first reference for the entry is a paper from J Allergy Clin Immunol. It's a great introduction to filaggrin and how it may be at the root of a large number of family-related eczema cases. This paper (Weidinger et al.) references a number of papers from Nature Genetics; the most important ones are from 2006, when, it appears, two overlapping groups reported finding loss-of-function mutations in the filaggrin gene that are associated with eczema. Filaggrin looks guilty to me. (See fascinating blog entry in the Nature system.)

But, as anyone with eczema knows, it's a complex condition; the underlying science appears just as complex. Weidinger et al. analyzed 476 German families: from each family, the parents and one child with AD. I haven't digested the paper fully; but of the 476 kids, roughly one-quarter had one of the two known loss-of-function filaggrin mutations. So there are evidently other molecular causes of eczema. Maybe there are yet-unmapped filaggrin mutations. Maybe there are mutations of other genes that screw up the same processes as mutated filaggrin. There are probably many, many paths to the same end.

What is filaggrin? It's a protein product of the FLG gene on the q-arm of chromosome 1. The gene itself is complicated, which is why scientists took a long time to sequence it. I look forward to learning more!

FLG is expressed as profilaggrin, a larger protein, in skin cells in the lower levels of the epidermis. As the skin cells move toward the stratum corneum, they start expressing different proteins and making lipids and other molecules to form barrier impermeable to pathogens such as viruses and bacteria. When skin cells reach their final state, before they slough off as skin flakes, the profilaggrin is chopped up into small bits called peptides, and these filaggrin peptides bind filaments of keratin inside the cells. The filaments then get cross-linked by enzymes--something like the way fiberglass and resin combine to make one godawfully tough material.

If you have a mutation in your filaggrin gene (these mutations appear to be dominant, from what I can tell) then your skin has a crappy fiberglass coating instead of a smooth, impermeable one. It lets water out; it lets pathogens and allergens in.

This skin defect may be at the root of eczema. As a baby, if your skin is defective, it lets in viruses and allergens, which induce inflammation. And then because of the chronic inflammation, you then develop the allergies and sensitivities that later manifest as the confusing food-, aero-allergen, and stress-related flareups of classic eczema.

So why does eczema affect 20% of children, and then mostly disappear--though not for me, nor 2% of adults? What happens as kids grow up?

Fascinating stuff! You can't blame the scientists for being interested. I just wish the problem was purely academic.

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