Professor Randy Blakely discusses the impact of gene variation (polymorphisms) on transporter proteins. Impact can be very subtle and is linked to regulatory processes.

In the last several years, we have understood better what the impact of gene variation, or polymorphisms, can be on transporter proteins and on other genes as well. The historical concept is that gene variation can lead to many different kinds of changes in the way a gene functions. It can eliminate the gene, it can result in a gene that doesn’t produce very much of the protein, it can affect certain features of the protein. I think some of that, in the last few years, we’ve begun to emphasize more when we have found mutations, polymorphisms that change the ability of the biogenic amine transporter proteins to be regulated. These proteins function quite normally, but when incoming signals that would normally turn them off or turn them on in an appropriate setting arrive, these mutations prevent that from occurring. So it’s a very subtle way in which mutation impacts protein function, and it’s something that I think many who study genetics of neuronal proteins forget. They tend to emphasize a loss of function; they’ll say it’s a defect, and when they say that, they tend to mean that the protein is gone, it’s lost, it can’t be replaced, or that you can’t bypass it in an interesting way. But if you understand the subtlety and the way in which mutations can influence proteins, for example we found serotonin transporter mutations or polymorphisms that result in an inability to be regulated by a specific enzyme. Well, knowing that, we can turn around and say, maybe we don’t need to go after the protein with a drug itself – the transporter protein – maybe we need to go toward the regulatory process in which it’s engaged and target our therapies there.

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