Anton-Scott Goustin–Jan 28, 2010
My "favorite gene" is on human chromosome 3q27. It encodes a moderate-sized phosphorylated glycoprotein (yes!) which is secreted at a high rate from hepatocytes, into the bloodstream. The gene is
called AHSG (in H. sapiens), Ahsg (mouse), or sometimes fetuin-A. The protein was discovered as the first fetal protein (yes!) in 1944 in Sweden, and published in Nature:
Pedersen, K.O. (1944). Fetuin, a New Globulin Isolated from Serum. Nature 154, 575.
We became interested in this gene in 1991 when we cloned the human cDNA using a homologous rat probe, and expressed the human ORF in insect cells. The cells produced a phosphorylated glycoprotein
which strongly blunted the tyrosine kinase (TK) activity of the insulin-activated insulin receptor (IR). The glycoprotein does not bind to the insulin site on the IR, but to the extracellular portion
of the beta subunit of the IR. It binds 5 times better to insulin-activated IR than to insulin-naive IR. We think it thus "picks out" the 1% of cell surface IR which are in functional complexes, and
selects them for blunting. When blunted, the TK is down-regulated, and instead there is SER phosphorylation of IRS-1 and -2 which acts to confound insulin's sharp edge.
In 2002, we showed that a mouse null for both alleles of Ahsg was quite the opposite of type 2 diabetes: it was super-sensitive to insulin! and the mouse failed to gain weight on a prolonged high-fat
(HF) diet:
Mathews, S.T., Singh, G.P., Ranalletta, M., Cintron, V.J., Qiang, X., Goustin, A.S., Jen, K.L., Charron, M.J., Jahnen-Dechent, W., and Grunberger, G. (2002). Improved insulin sensitivity and
resistance to weight gain in mice null for the Ahsg gene. Diabetes 51, 2450-2458.
Many clinical groups have now looked at AHSG gene function, and corroborated our prediction that this gene helps to underly insulin resistance and obesity, including:
Lavebratt, C., Wahlqvist, S., Nordfors, L., Hoffstedt, J., and Arner, P. (2005). AHSG gene variant is associated with leanness among Swedish men. Hum Genet 117, 54-60.
