A variant primary structure of apolipoprotein C-II in individuals of African descent
Insights
Researchers identified a new form of apolipoprotein C-II (apolipoprotein C-II2) in patients with hypertriglyceridemia. This genetic variant, apolipoprotein C-II2, is prevalent in individuals of African ancestry and may influence lipid metabolism.
Area of Science:
- Biochemistry
- Genetics
- Human Physiology
Background:
- Apolipoprotein C-II (apoC-II) is a crucial activator of lipoprotein lipase (LPL).
- Mutations in apoC-II can lead to hypertriglyceridemia, a condition characterized by high levels of triglycerides in the blood.
- Eruptive xanthomata are skin lesions associated with severe hypertriglyceridemia.
Purpose of the Study:
- To identify and characterize novel isoforms of apolipoprotein C-II.
- To investigate the prevalence and genetic basis of a newly identified apoC-II isoform.
- To explore the potential association of this apoC-II isoform with hypertriglyceridemia.
Main Methods:
- Isolation and characterization of apolipoprotein C-II isoforms from very low-density lipoproteins (VLDL).
- Amino acid sequencing to identify structural differences between isoforms.
- Genetic analysis including family studies and population screening using isoelectric focusing.
- Comparison of isoform distribution in patients with hypertriglyceridemia and normolipidemic individuals.
Main Results:
- An isoform, designated apolipoprotein C-II2, was isolated from VLDL of hypertriglyceridemic patients of African ancestry.
- Apolipoprotein C-II2 differs from the common form (apolipoprotein C-II1) by a glutamine-for-lysine substitution at residue 55.
- This substitution suggests an allelic relationship between the genes for apoC-II1 and apoC-II2.
- Apolipoprotein C-II2 was found in equal amounts with apoC-II1 in affected patients and heterozygotes, indicating autosomal transmission.
- The apoC-II2 polymorphism was detected in normolipidemic Black individuals but not in Caucasian hyperlipidemic subjects.
Conclusions:
- A novel apolipoprotein C-II isoform (apoC-II2) has been identified, associated with hypertriglyceridemia in individuals of African ancestry.
- The genetic basis appears to be an allelic polymorphism, likely with monogenic autosomal transmission.
- The prevalence of this polymorphism primarily in Black populations suggests potential positive Darwinian selection.
- Further research is needed to determine if this apoC-II polymorphism modifies the development of hyperlipemia.
Abstract:
We have isolated an isoform of the protein activator of lipoprotein lipase, apolipoprotein C-II, from the very low density lipoproteins of four patients of African ancestry with hypertriglyceridemia and eruptive or pedunculated xanthomata. This protein, which we designate apolipoprotein C-II2, differs from the previously recognized species, which we denote apolipoprotein C-II1, by substitution of glutamine for lysine at residue 55, a mutation which would require only a single-base substitution in the structural gene for apolipoprotein C-II1. Each of the patients in whom apolipoprotein C-II2 was found had approximately equal amounts of apolipoprotein C-II1 and apolipoprotein C-II2 among the apoproteins of the very low density lipoproteins, suggesting that the structural genes for these proteins are allelic. Two additional apparent heterozygotes were found among the first-degree relatives of each of two of the patients in patterns compatible with monogenic autosomal transmission. Approximately equal amounts of apolipoproteins C-II2 and C-II1 were also found by isoelectric focusing in 6 of a casual series of 50 normolipidemic blacks, but none or only trace amounts of apolipoprotein C-II2 were found in 500 samples from Caucasian subjects with hyperlipidemia. These findings suggest that this polymorphism is distributed primarily among blacks, possibly reflecting some positive Darwinian selection pressure. Whether this polymorphism has a modifying effect upon the development of hyperlipemia remains to be determined.
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