A very recent publication on a possible PD-related polymorphism in the gene for glycoprotein-P (aka MDR1) that I mentioned in an earlier post on this thread has just appeared in the Jan. 26 issue of Science. It is from the Michael Gottesman lab at the National Cancer Institute of NIH:

Chava Kimichi-Sarfaty, Jung Mi Oh, et al. A "Silent " Polymorphism in the MDR1 Gene Changes Substrate Specificity, Science, 315, 525 (2007).

This particular gene polymorphism, C3435T, where Cytidine is replaced by Thymidine at position 3435 in the DNA sequence of the gene, is one of more than 50 other single-nucleotide polymorphisms (SNPs) in the MDR1 (multi-drug resistance) gene.

C3435T is a "synonymous" SNP, that is, it does not alter the amino acid coded for in the protein produced from the gene, although one of the DNA bases (letters) in the three-lettered amino acid "codon" is changed. The more common codon for that particular amino acid has a C in that position, and changing it to a T creates a less common codon, but which is still "translated" as the same amino acid. For that reason, such an SNP is referred to as "silent", since the number and sequence of amino acid "building blocks" remains unchanged.

What they discovered is that when the MDR1 gene with this rare codon polymorphism also contains two other, less rare, silent polymorphisms, the resulting protein exhibits different binding specificity. It changes the way this membrane protein "pump" ineracts with three different drugs, paclitaxel(taxol), verapimil, and cyclosporin A, when compared with the protein produced from the "wild type" (normal) gene.

Other experiments showed that the shape of the protein was also altered. Both of these results were unexpected, since it is generally accepted that two proteins with the same amino acid structure will have the same shape, or conformation, and will exhibit identical interactions with other molecules.

They proposed that silent mutations in which one or more less common, but still translatable, SNPs occur may alter the timing of the RNA-to-protein translation process such that "pauses" at critical points may result in changes in specific steps of the "folding" process of the protein, with the result that conformational differences are produced.

They speculate that such subtle changes may be related to inherited diseases in which some cases are clearly assocoated with defined gene mutations, while others are not, and appear to be "sporadic" (e.g. PD)