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An apolipoprotein CII mutation, CIILys19----Thr' identified in patients with hyperlipidemia
R A Hegele1, P W Connelly, G F Maguire
1Department of Medicine, University of Toronto, Canada.
Insights
A novel apolipoprotein C-II (apoCII) variant, C2K19T, was identified in hyperlipidemic patients. This mutation, absent in normolipemic individuals, may contribute to hyperlipoproteinemia development, potentially interacting with other genetic factors.
Area of Science:
- Biochemistry
- Genetics
- Metabolic Disorders
Background:
- Hyperlipoproteinemia encompasses a group of genetic disorders characterized by elevated plasma lipid levels.
- Apolipoprotein C-II (apoCII) is crucial for lipoprotein metabolism, particularly in activating lipoprotein lipase.
Purpose of the Study:
- To investigate the genetic basis of hyperlipoproteinemia in affected individuals.
- To identify and characterize novel variants of apolipoprotein C-II associated with hyperlipidemic phenotypes.
Main Methods:
- Isoelectric focusing was used to detect apoCII isoforms in hyperlipidemic patients.
- Protein sequencing and allele screening were performed to characterize the identified apoCII variant and its prevalence.
Main Results:
- Five hyperlipidemic patients exhibited a variant apoCII isoform (C2K19T) with a charge alteration at amino acid residue 19 (Lys to Thr).
- This C2K19T mutation was not found in 160 screened normolipemic apoCII alleles.
- The substitution occurs in a proposed lipid-binding domain of apoCII.
Conclusions:
- The C2K19T apoCII variant is associated with hyperlipoproteinemia.
- This mutation may play a role in hyperlipoproteinemia pathogenesis, possibly in conjunction with other genetic factors like apolipoprotein E mutations.
Abstract:
Five hyperlipidemic patients (one with Type III, three with Type IV, and one with Type V hyperlipoproteinemia) were found on isoelectric focusing to have both the normal isoform of apolipoprotein CII and a second isoform whose isoelectric point was consistent with a single charge change. The structure of the apolipoprotein CII variant was determined to be the same as normal apolipoprotein CII except for replacement of the normal Lys at amino acid residue 19 by Thr (C2K19T). The mutation was absent from 160 apoCII alleles screened from normolipemic subjects. The C2K19T substitution occurs in a domain of apolipoprotein CII postulated to contain a lipid-binding amphipathic alpha-helix. The presence of C2K19T in unrelated hyperlipidemic patients of various racial backgrounds suggests that, in combination with other factors such as mutations in apolipoprotein E, it plays a role in the development of hyperlipoproteinemias.