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We identified a large family in which a hitherto unreported point mutation of the LDL receptor gene (Asp235→Glu) cosegregated with moderately elevated serum LDL cholesterol concentration. Within one generation, the mean serum total and LDL cholesterol levels in four heterozygous carriers of this mutation (7.76±1.46 and 5.89±1.56 mmol/L, respectively) were significantly (P &lt;.05) higher than the corresponding concentrations in their five nonaffected siblings (5.81±0.57 and 3.77±0.54 mmol/L, respectively). Lipid levels in carriers of the Asp235→Glu mutation were, however, markedly lower than the corresponding total and LDL cholesterol levels (about 12 and 10 mmol/L, respectively) in heterozygous patients with the two common LDL receptor mutations (FH-Helsinki and FH-North Karelia). None of the four siblings in the age range of 54 to 69 years had experienced a myocardial infarction, although symptoms suggestive of coronary artery disease were present in two and tendon xanthomas were found in one. Expression of the mutant receptor in COS cells indicated an approximately 50% to 70% reduction of LDL-binding activity compared with the normal receptor. One patient (female, aged 39 years) had severe hypercholesterolemia in the range of 13 to 20 mmol/L when untreated, extensive coronary artery disease as demonstrated by angiography, and extensor tendon xanthomatosis. In addition to the Asp235→Glu mutation, she was found to have a de novo deletion of exons 14 and 15 in her other LDL receptor allele. In this subject, the total LDL receptor activity of mitogen-stimulated blood lymphocytes was very low. In conclusion, along with another LDL receptor gene mutation (FH-Espoo or deletion of exon 15) described by us previously, the Asp235→Glu mutation (designated as FH-Keuruu) indicates that moderate varieties of inherited hypercholesterolemia may result from LDL receptor gene mutations of mild expression.

arteriosclerosis, thrombosis, and vascular biology

Familial Moderate Hypercholesterolemia Caused by Asp235→Glu Mutation of the LDL Receptor Gene and Co-occurrence of a De Novo Deletion of the LDL Receptor Gene in the Same Family