Characteristics of LDL receptor mutations in Japanese familial hypercholesterolemia

In Japan, as consanguineous marriages are relatively frequent, it is possible to observe comparatively frequently the true homozygotes of FH. These patients inherit two identical LDL receptor gene mutations from their parents. By analyzing the LDL receptor mutations in 14 families with true homozygotes, we identified 9 different mutations. The true homozygotes are useful for characterizing the phenotype of each mutation due to the uniformity of the gene mutations. By analyzing these gene mutations together with their phenotypes in the fibroblasts of the patients, we could characterize several unique phenotypes of the LDL receptor such as internalization-defective, recycling-impaired, processing-impaired, truncated, degradation-enhanced and protein synthesis-impaired forms. From these studies we could determine the structure/function relationship of the LDL receptor protein.It is known that in some selected populations, limited numbers of mutations of LDL receptor gene predominate. In such areas, diagnosis of FH is easier. To determine if some common mutations exist in Japan, we examined the frequency of each mutation identified in our FH homozygotes. By analyzing 120 unrelated FH heterozygotes, we found that the five mutations, 1) 1845+2T→C, 2) K790X, 3) C317S, 4) P664L, and 5) L547V, are relatively frequent. These mutations comprised about 30% of the mutant alleles of Japanese FH. Although the frequency of each mutation is not as high as those of common mutations found in populations such as French Canadians or Afrikaaners, these frequencies reflect a sort of “founder effect” as Japanese people are mostly uniracial and Japan is geographically isolated.The natures of the LDL receptor gene mutations contributed to the clinical manifestation of FH in patients. Individuals bearing the receptor-defective type L547V mutation manifested lower plasma levels of LDL-cholesterol and had less aggressive coronary atherosclerosis than those bearing receptor-negative type mutations.