The exons of the low‐density‐lipoprotein‐(LDL)‐receptor gene from a Japanese patient with homozygous familial hypercholesterolemia were amplified by the polymerase chain reaction (PCR), and their nucleotide sequences were determined. A point mutation from G to C was found in exon 9, which was expected to change Asp at position 412 to His. This amino acid change occurred within the epidermal‐growth‐factor‐precursor homology domain of the LDL receptor, slightly impairing the processing from the precursor to the mature form and causing rapid degradation of the mature form in the fibroblasts of the patient. The mutant LDL‐receptor gene transfected into COS‐1 cells expressed a LDL‐receptor protein with the same properties as the protein expressed in the fibroblasts of the patient
impaired processing and rapid degradation of the synthesized receptor protein. The mutation was identified in family members of the patient by dot‐blot hybridization of PCR‐amplified DNA with the mutant oligonucleotide. The family members carrying the mutant gene showed higher serum cholesterol levels than the others. However, their cholesterol levels were also greatly influenced by the apolipoprotein‐E phenotype. Copyright © 1992, Wiley Blackwell. All rights reserved