Hmgcr^tm1.1Radb

A lysine to arginine mutation at amino acid 89 (AAG to AGG; K89R) was introduced in exon 3 and a lysine to arginine mutation at amino acid 248 (AAA to AGA; K248R) was introduced in exon 8. In addition, a FRT-flanked Neo cassette was introduced upstream of exon 3 and a FRT3-flanked Hygro cassette was inserted downstream of exon 8. Flp-mediated recombination removed both the Neo and Hygro resistance genes. These mutations abolish sterol-induced ubiquitination and subsequent degradation of HMGCR. Immunoblot analysis indicate an approximate 6- and 14-fold accumulation of HMGCR protein in the livers of heterozygous and homozygous mice, respectively, despite reduced mRNA levels. (J:235015)