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Screening for functional sequence variations and mutations in ABCA1
Mario C O Probst1, Harald Thumann, Charalampos Aslanidis
1Institute of Clinical Chemistry and Laboratory Medicine, University of Regensburg, Franz-Josef Strauss-Allee 11, Regensburg DE-93053, Germany.
Insights
This study identifies novel genetic variations in the ABCA1 gene associated with altered high-density lipoprotein cholesterol (HDL-C) levels. These findings contribute to understanding HDL deficiency and related cardiovascular risks.
Area of Science:
- Genetics
- Molecular Biology
- Cardiovascular Disease
Background:
- Mutations in the ATP-binding cassette transporter 1 (ABCA1) gene cause genetic HDL-deficiency syndromes.
- These syndromes are linked to low HDL-C levels, cardiovascular disease, and splenomegaly.
- ABCA1 facilitates cholesterol and phospholipid transport, crucial for HDL metabolism.
Purpose of the Study:
- To identify novel polymorphisms and mutations in functionally relevant regions of the ABCA1 gene.
- To investigate the association of these variations with altered HDL-C levels.
- To create a comprehensive online archive of ABCA1 sequence variations.
Main Methods:
- Screening of promoter and C-terminal regions of the ABCA1 gene for sequence variations.
- Analysis of cohorts including individuals with altered HDL levels, healthy donors, and octogenarians.
- Electrophoretic mobility shift assays to assess ZNF202 binding to a VNTR polymorphism.
Main Results:
- Identified three novel SNPs in the ABCA1 promoter region (G1047C, C1152T, C1440T), with G1047C, C1152T, and C1440T showing increased prevalence in low HDL cohorts.
- Discovered two novel sequence variations (F2163S, V2244I) in the C-terminal region in one cardiovascular disease patient.
- Reported three novel mutations (W590L, W840R, R1068C) in patients with HDL deficiency.
Conclusions:
- Novel ABCA1 gene variations in promoter and coding regions are associated with altered HDL-C levels and HDL deficiency.
- These findings enhance the understanding of ABCA1's role in lipid metabolism and cardiovascular health.
- An online ABCA1 mutant archive is established to aid research and molecular diagnostics.
Abstract:
Mutations in the ATP-binding cassette 1 transporter gene (ABCA1) are responsible for the genetic HDL-deficiency syndromes, which are characterized by severely diminished plasma HDL-C levels and a predisposition to cardiovascular disease and splenomegaly. The ABCA1 gene contains 50 exons and codes for a 2261-amino acid long membrane protein that facilitates phospholipid and cholesterol transport. Several mutations have been identified so far as responsible either for Tangier disease or for reduced HDL levels. We have selectively looked for additional polymorphisms in functionally relevant regions of the gene in cohorts constituted of individuals with altered HDL levels as well as healthy blood donors and octogenarians, and screened for mutations in the complete coding region of selected individuals with extremely aberrant HDL levels. In the promoter region, which is important for regulation of gene expression, we have identified several polymorphisms including one VNTR polymorphism, located at a putative ZNF202 binding site, which displayed different binding of ZNF202 in an electromobility shift assay. Three novel SNPs were discovered in the promoter region (G1047C, C1152T and C1440T). The prevalence of exchange G1047C (G-395C) was found significantly increased in probands with low HDL compared to probands with high HDL. Exchanges C1152T (C-290T) and C1440T (C-7T) were significantly more frequent in the cohort with low HDL compared to healthy blood donors and octogenarians. In the C-terminal part of ABCA1, known to interact with other proteins, two novel sequence variations (F2163S and V2244I) have been found in one phenotype related to cardiovascular disease, but none in the aforementioned cohorts. In one individual with extremely high HDL levels, the V771M polymorphism was found in a homozygous state. In patients with HDL deficiency, three novel mutations have been identified (W590L, W840R and R1068C). To facilitate further research in ABCA1 sequence variations and expand our understanding of their effects, we are introducing a webpage archive (http://www.abca1-mutants.all.at) containing all sequence variations reported in ABCA1 so far. This webpage provides a more recent and detailed summary of sequence variations and mutations in ABCA1 than existing databases and should also be of interest for molecular diagnosis of ABCA1-related HDL deficiency.
