Frequent Mutation in the ABCC6 Gene (R1141X) Is Associated With a Strong Increase in the Prevalence of Coronary Artery Disease

Abstract

Background-Pseudoxanthoma elasticum (PXE) is an inborn disorder of the connective tissue with specific skin, ocular, and cardiovascular disease (CVD) manifestations. Recently, we and others have identified mutations in the gene coding for the ABCC6 transporter in PXE patients with ocular and skin involvement. In the Netherlands, as in the rest of Europe, a particular premature truncation variant ABCC6 (R1141X) was found in a large cohort of PXE patients. Given the association between CVD and PXE, we hypothesized that heterozygosity of this ABCC6 mutation could also confer an increased risk for CVD. Methods and Results-To assess the relationship between the frequent R1141X mutation in the ABCC6 gene and the prevalence of premature coronary artery disease (CAD), we conducted a case-control study of 441 patients under the age of 50 years who had definite CAD and 1057 age-and sex-matched population-based controls who were free of coronary disease. Strikingly, the prevalence of the R1141X mutation was 4.2 times higher among patients than among controls (3.2% versus 0.8%; PϽ0.001). Consequently, among subjects with the R1141X mutation, the odds ratio for a coronary event was 4.23 (95% CI: 1.76 to 10.20, Pϭ0.001). Conclusion-The

The ERK1/2-Hepatocyte Nuclear Factor 4α Axis Regulates Human ABCC6 Gene Expression in Hepatocytes

“…In these cases an increase of gene expression might diminish the severity of the PXE phenotype. Heterozygous carriers were shown to have increased risk of developing coronary artery disease (46,47). Patients suffering from ␤-thalassemia frequently develop secondary PXE without mutations in the ABCC6 gene may be due to chronic oxidative stress (48).…”

Assessment of a rapid-cycle PCR assay for the identification of the recurrent c.3421C>T mutation in the ABCC6 gene in pseudoxanthoma elasticum patients

“…This is a possible factor for genotype misinterpretation that has to be taken into consideration when designing a versatile rapid-cycle assay suitable for fast routine diagnostics. The ABCC6del23-29 deletion, which was found to be a common mutation in PXE patients from the United States, 15 is a 16.5-kb deletion leading to an omission of exons [23][24][25][26][27][28][29]. In order to avoid misinterpretation of the c.3421C4T genotype due to a loss of at least one exon 24 allele, we analyzed our cohort for the occurrence of the ABCC6del23-29 mutation.…”

“…Trip et al 27 recently analyzed the frequency of this c.3421C4T mutation in a Dutch population and found eight heterozygous carriers within their c.3421C4T genotyping in PXE patients C Götting et al cohort consisting of 2114 control chromosomes. These divergent results indicate the potential need for a population-specific control cohort when analyzing ABCC6 gene mutations and for further investigations on the frequency of the c.3421C4T mutation in different ethnic groups.…”

“…29 Just recently, a case-control study in a Dutch population revealed that the c.3421C4T mutation in a heterozygous state is associated with a strong increase in the prevalence of coronary artery disease. 27 These results lead us to consider the determination of the c.3421C4T mutation in routine screening for cardiac risk factors. The rapid determination of risk factors is a very important feature for young patients with myocardial infarcts of unknown origin and can be effortlessly performed with our newly developed rapid-cycle assay.…”

“…[7][8][9][14][15][16][17][18] A frequent mutation detected in the ABCC6 gene in PXE patients is the nonsense mutation c.3421C4T (p.R1141X), resulting in a truncated protein that lacks the second ATP-binding domain of the native MRP6. [7][8][9]19,20 Another mutation, which is frequently found in American PXE patients, is a large deletion including exons [23][24][25][26][27][28][29]17 which also leads to a loss of the second ATP-binding site of MRP6. PXE is a rare disease with a highly variable phenotype.…”