Wednesday, February 16, 2011

PCSK, cholesterol homeostasis and osteoporosis

Today, I saw a news release on a series of articles concerning the PCSK gene family published by Dr. Nabil Seidah's group at the Institut de recherches cliniques de Montréal. The combined body of work suggests that the PCSK enzymes could influence health from cholesterol homeostasis to osteoporosis.

PCSK stands for proprotein convertase subtilisin/kexin. This means that it enzymatically converts a larger proprotein into a smaller functional entity. PCSK9 is certainly the most well publicized member of this family with much known about genetic variants associating with myocardial infarction, heart disease and plasma lipid levels, particularly LDL-cholesterol. PCSK9 interacts with the LDL-cholesterol receptor.

PCSK9 also shows decreased expression in a circadian rhythmic fashion in mouse liver depleted for Mir122. This comes from a report by Gatfield, Schibler, et al. 2009 Genes Dev. 23:1313-26.

Here are some other interesting bits about members of the PCSK gene family.

PCSK2 - homolog of nematode gene C51E3.7 which is involved in determination of adult lifespan. SNPs in PCSK2 may increase susceptibility to myocardial infarction and type 2 diabetes, which are both age-related afflictions. A QTL for HDL has been mapped to the vicinity of Pcsk2 in mouse: Hdlq19.

Interestingly, some of my own work on literature mining with Biomax BioLT tool indicated that both PCSK7 and PCSK1N have relationships with HDL-cholesterol. A QTL for HDL at the PCSK7 locus has been described.

Heterozygous knock-out mice for Pcsk1 show increased adipose mass. Transgenic expression in mice of Pcsk1n driven by an actin promoter yielded adult-onset obesity. This gene, in human, was recently proposed as a candidate obesity/type 2 diabetes (T2DM) genes by Chang Hsu (2011 Diabetes, in press) but did not pass their test for Fst measures of positive selection.

An interesting paper by Tiffin, Hide, et al. (2006) suggested that PCSK2 and PCSK7 are candidate obesity and T2DM genes.

Certainly interesting phenotypes here. Keep your eyes on these genes.

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