4-Phenylbutyrate restores the functionality of a misfolded mutant low-density lipoprotein receptor.

摘要: Familial hypercholesterolemia is an autosomal dominant disease caused by mutations in the gene encoding low-density lipoprotein receptor. To date, more than 900 different have been described. Transport-defective (class 2) causing partial or complete retention of receptor endoplasmic reticulum are predominant class mutations. In a cell culture system (Chinese hamster ovary cells), we show that chemical chaperones able to mediate rescue transport-defective mutant (G544V), and ability obtain mutation dependent. particular, low molecular mass fatty acid derivative 4-phenylbutyrate mediated marked increase transport G544V-mutant plasma membrane. Thirty per cent was escape from reach surface. The rescued had reduced stability, but found be as efficient wild-type binding internalizing lipoprotein. addition 4-phenylbutyrate, also studied 3-phenylpropionate 5-phenylvalerate, compared their effect on with overall expression histone deacetylase inhibitor activity. No correlation found. Our results indicate these agents not solely induce proteins involved intracellular transport, rather could due direct chaperone These data suggest possible it might feasible develop pharmacologic treat familial patients class 2