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Published on: September 15, 2018
Compound heterozygous familial hypercholesterolemia and familial defective apolipoprotein B-100 produce exaggerated
1Lipid Unit, Department of Endocrinology, Singapore General Hospital, Singapore 169608, Republic of Singapore. eshyong@pacific.net.sg
Insights
Familial hypercholesterolemia (FH) and familial defective apolipoprotein B-100 (FDB) are rare genetic disorders. This study identifies a family with both FH and FDB, revealing how these mutations impact cholesterol levels and family members.
Area of Science:
- Genetics
- Molecular Biology
- Cardiovascular Medicine
Background:
- Familial hypercholesterolemia (FH) and familial defective apolipoprotein B-100 (FDB) are distinct genetic lipid disorders.
- Individuals inheriting mutations for both FH and FDB are exceptionally rare.
- This study investigates a family exhibiting co-inheritance of FH and FDB mutations.
Observation:
- Genetic analysis identified LDL receptor mutations in some family members and apolipoprotein B-100 mutations in others.
- The apolipoprotein B-100 mutation was functionally assessed using a cell proliferation assay, showing reduced U937 cell proliferation.
- The index case presented with mutations linked to both FH and FDB.
Findings:
- A sister with an LDL receptor mutation had elevated LDL-cholesterol (4.07 mmol/L).
- Four relatives with hyperlipidemia carried the apolipoprotein B-100 mutation (Arg(3500)-->Trp), exhibiting reduced LDL function.
- The index case, possessing both FH and FDB mutations, displayed the highest LDL-cholesterol levels (9.47 mmol/L).
Implications:
- The co-existence of FH and FDB should be considered in families with hypercholesterolemia, particularly when mutations in the LDL receptor gene are present in some but not all affected individuals.
- Exaggerated hypercholesterolemia in FH families may indicate co-existing FDB mutations.
- Understanding these combined genetic defects is crucial for accurate diagnosis and management of severe hyperlipidemia.
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 (Asp(407)-->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 (Arg(3500)-->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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