Intron 14 CETP splicing defect is found in 3.5% of Japanese patients with marked hyperalphalipoproteinemia and an estimated 1/42,000 homozygote frequency (Atherosclerosis 1993)

Cholesteryl ester transfer protein (CETP) deficiency, which has been found only in Japan, is characterized by marked hyperalphalipoproteinemia (HALP) and abnormalities of both low density and high density lipoproteins. We have reported that this deficiency is commonly associated with a G-->A mutation at the intron 14 splice donor site of the CETP gene (Yamashita et al., Biochem. Biophys. Res. Commun., 170 (1990) 1346-1351). In the current study, we determined the frequency of this mutation in Japanese subjects by using polymerase chain reaction. A single primer-template mismatch of one base pair from the CETP gene mutation permitted the introduction of a cleavage site for Nde I in mutant alleles but not in normal ones. Out of 171 patients with marked HALP whose serum HDL-cholesterol was more than 100 mg/dl, 6 (3.5%) subjects were homozygous and 48 (28.1%) were heterozygous for this mutation. Furthermore, in unrelated 512 healthy Japanese subjects, 5 (0.98%) were identified as heterozygotes. Relative allelic frequency of A at the intron 14 splice donor site was 0.0049 and the frequency of homozygous CETP deficiency was estimated to be approximately 1/42,000. These results demonstrate that this common mutation may be frequent in the Japanese population. Although HALP is very heterogenous, this mutation could be one of the major causes of marked HALP.