Clinical Chemistry
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Clinical Chemistry 47: 438-443, 2001;
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(Clinical Chemistry. 2001;47:438-443.)
© 2001 American Association for Clinical Chemistry, Inc.

Articles

Compound Heterozygous Familial Hypercholesterolemia and Familial Defective Apolipoprotein B-100 Produce Exaggerated Hypercholesterolemia

E. Shyong Tai1,2,a, Evelyn S.C. Koay2,3,2, Edmund Chan1, Tzer Jing Seng3, Lih Ming Loh1, Sunil K. Sethi2,3 and Chee Eng Tan1

1 Lipid Unit, Department of Endocrinology, Singapore General Hospital, Singapore 169608, Republic of Singapore.

2 Department of Laboratory Medicine, National University Hospital, Singapore 119074, Republic of Singapore.

3 Department of Pathology, National University of Singapore, Singapore 119260, Republic of Singapore.
a Author for correspondence. Fax 65-227-3576; e-mail eshyong{at}pacific.net.sg.

Background: Familial hypercholesterolemia (FH) and familial defective apolipoprotein B-100 (FDB) represent ligand-receptor disorders that are complementary. Individuals with both FH and FDB are unusual. We report a family with both disorders and the impact of the mutations on the phenotypes of the family members.

Methods: We used single strand conformation polymorphism (SSCP) and denaturing gradient gel electrophoresis (DGGE) for genetic analysis of all 18 exons and the promoter region of the LDL receptor and DGGE for genetic analysis of the apolipoprotein B-100 (apo B-100) gene. The functional significance of the apo B-100 mutation was studied using a U937 cell proliferation assay. Fasting serum lipid profiles were determined for the index case and seven first-degree relatives.

Results: One of the patient’s sisters had a missense mutation (Asp407->Lys) in exon 9 of the LDL receptor and a serum LDL-cholesterol concentration of 4.07 mmol/L. Four other first-degree relatives had hyperlipidemia but no LDL-receptor mutation. However, these subjects had a mutation of the apo B-100 gene (Arg3500->Trp). The cell proliferation rate of U937 cells fed with LDL from other subjects with the same mutation was fourfold less than that of controls. The index case had both FH- and FDB-related mutations. Her serum LDL-cholesterol (9.47 mmol/L) was higher than all other relatives tested.

Conclusions: Existence of both FH and FDB should be considered in families with LDL-receptor mutations in some but not all individuals with hypercholesterolemia or when some individuals in families with FH exhibit exaggerated hypercholesterolemia.






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