Update of Japanese common LDLR gene mutations and their phenotypes: Mild type mutation L547V might predominate in the...

We investigated the LDLR gene mutations in 205 unrelated Japanese FH (familial hypercholesterolemia) heterozygotes to see if there is a prevalence of common mutations in the Japanese population. A total of 53 different small mutations (<25bp) and 10 kinds of large deletions (>25bp) were identified. Among them there were eight relatively frequent mutations: C317S, c.1845+2T>C, K790X, L547V, P664L, D412H, c.2312-3C>A and V776M. The patients with these mutations comprised 32% of the total FH heterozygotes investigated. Comparison of clinical phenotypes of the eight frequent mutations disclosed that a missense mutation, L547V, manifested a milder phenotype than the other mutations. The mild clinical phenotype was shown to be based on the high level of receptor activity remaining on the patient's cell surfaces. When we examined the presence of common mutations in a general population, the L547V mutation was detected with unexpectedly higher frequency than the other mutations, suggesting an underestimation of the frequency of this mutation in FH heterozygote patients. In conclusion, although there is a broad spectrum of LDLR gene mutations in the Japanese population, eight common mutations were observed. Among them, a mild phenotype mutation, L547V, might predominate in the Japanese population.