A novel nonsense mutation (G181X) in the human cholesteryl ester transfer protein gene in Japanese...

Cholesteryl ester transfer protein (CETP) plays an important role in regulating the concentration and composition of high density lipoprotein (HDL) and low density lipoprotein (LDL). Although several genetic abnormalities causing CETP deficiency have been identified in the Japanese subjects with a marked hyperalphalipoproteinemia (HALP), there are many CETP-deficient subjects for whom the genetic abnormalities have not been clarified. In the present study, we analyzed the molecular basis of an HALP subject without CETP activity and mass, and found a novel mutation in the CETP gene. This novel mutation (G181X) was a G-to-T substitution at codon 181 of exon 6 which replaced a codon for glycine (GGA) with a premature stop codon (TGA). The G181X mutation created a new cutting site by restriction enzyme MaeIII. To estimate the frequency of G181X, we investigated unrelated 294 HALP (HDL-cholesterol > or = 2.59 mmol/L = 100 mg/dl) subjects by restriction fragment length polymorphism (RFLP) analysis with Mae III. One (0.34%) HALP subject was homozygous and four (1.36%) were heterozygous for this mutation. The allelic frequency of a G-to-T substitution at codon 181 of exon 6 was 0.0102 in HALP subjects. From the lipid analysis of the proband and the homozygote, it was clarified that the G181X mutation had dominant effects on HDL and LDL metabolism, similar to a G-to-A substitution at the 5' splice donor site of the intron 14 (1451 + 1G-->A). In conclusion, the G181X mutation is one of causes of HALP in the Japanese HALP subjects, having dominant effects on lipid metabolism.