tailieunhanh - Báo cáo khoa học: 4-Phenylbutyrate restores the functionality of a misfolded mutant low-density lipoprotein receptor

Familial hypercholesterolemia is an autosomal dominant disease caused by mutations in the gene encoding the low-density lipoprotein receptor. To date, more than 900 different mutations have been described. Transport-defective mutations (class 2) causing partial or complete retention of the receptor in the endoplasmic reticulum are the predominant class of muta-tions. | ỊFEBS Journal 4-Phenylbutyrate restores the functionality of a misfolded mutant low-density lipoprotein receptor Kristian Tveten 0ystein L. Holla Trine Ranheim Knut E. Berge Trond P. Leren and Mari A. Kulseth MedicalGenetics Laboratory Department of MedicalGenetics Rikshospitalet-Radiumhospitalet MedicalCenter Oslo Norway Keywords chemical chaperone familial hypercholesterolemia G544V low-density lipoprotein receptor 4-phenylbutyrate Correspondence M. A. Kulseth Department of Medical Genetics Rikshospitalet-Radiumhospitalet MedicalCenter N-0027 Oslo Norway Fax 47 23075561 Tel 47 23075542 E-mail Received 25 October 2006 revised 7 February 2007 accepted 9 February 2007 doi Familial hypercholesterolemia is an autosomal dominant disease caused by mutations in the gene encoding the low-density lipoprotein receptor. To date more than 900 different mutations have been described. Transportdefective mutations class 2 causing partial or complete retention of the receptor in the endoplasmic reticulum are the predominant class of mutations. In a cell culture system Chinese hamster ovary cells we show that chemical chaperones are able to mediate rescue of a transport-defective mutant G544V and that the ability to obtain rescue is mutation dependent. In particular the low molecular mass fatty acid derivative 4-phenylbu-tyrate mediated a marked increase in the transport of G544V-mutant low-density lipoprotein receptor to the plasma membrane. Thirty per cent of the mutant receptor was able to escape from the endoplasmic reticulum and reach the cell surface. The rescued receptor had reduced stability but was found to be as efficient as the wild-type low-density lipoprotein receptor in binding and internalizing low-density lipoprotein. In addition to 4-phenylbutyrate we also studied 3-phenylpropionate and 5-phenylvalerate and compared their effect on rescue of the G544V-mutant low-density lipoprotein receptor with .