FAMILIAL HYPERCHOLESTEROLEMIA IN CHINA - IDENTIFICATION OF MUTATIONS IN THE LDL-RECEPTOR GENE THAT RESULT IN A RECEPTOR-NEGATIVE PHENOTYPE

Familial hypercholesterolemia (FH), caused by many different mutations in the low-density lipoprotein (LDL)-receptor gene, invariably leads to severe premature coronary heart disease (CHD) in homozygous individ uals. Heterozygous FH patients are less severely affected but are stil l at increased risk of CHD in most populations. Although FH homozygote s in China are affected similarly to those elsewhere, heterozygotes ar e not detected in the general population and obligate heterozygotes ar e often not hypercholesterolemic by Western standards. Mutations in th e LDL-receptor genes of 10 homozygous FH patients from the Jiang-su pr ovince of China and their heterozygous parents were analyzed. These in clude one large and two minor deletions and eight point mutations: fou r are predicted to introduce a premature stop codon, five to result in a single amino acid substitution or deletion, and one to produce a pr otein with an abnormal cytoplasmic tail. Expression of the mutant LDL- receptor cDNAs in vitro confirmed that these mutations impaired LDL-re ceptor function and that several would cause a receptor-negative pheno type. Thus, the lack of clinical expression in obligate FH heterozygot es is not due to unusually ''mild'' mutations in the LDL-receptor gene , and other genetic or environmental factors must therefore be importa nt in determining phenotypic expression.