A Novel Splice-Site Mutation in Angiotensin I-Converting Enzyme (ACE) Gene, c.3691+1G>A (IVS25+1G>A), Causes a Dramatic Increase in Circulating ACE through Deletion of the Transmembrane Anchor

Abstract

BackgroundAngiotensin-converting enzyme (ACE) (EC 4.15.1) metabolizes many biologically active peptides and plays a key role in blood pressure regulation and vascular remodeling. Elevated ACE levels are associated with different cardiovascular and respiratory diseases.Methods and ResultsTwo Belgian families with a 8-16-fold increase in blood ACE level were incidentally identified. A novel heterozygous splice site mutation of intron 25 - IVS25+1G>A (c.3691+1G>A) - cosegregating with elevated plasma ACE was identified in both pedigrees. Messenger RNA analysis revealed that the mutation led to the retention of intron 25 and Premature Termination Codon generation. Subjects harboring the mutation were mostly normotensive, had no left ventricular hypertrophy or cardiovascular disease. The levels of renin-angiotensin-aldosterone system components in the mutated cases and wild-type controls were similar, both at baseline and after 50 mg captopril. Compared with non-affected members, quantification of ACE surface expression and shedding using flow cytometry assay of dendritic cells derived from peripheral blood monocytes of affected members, demonstrated a 50% decrease and 3-fold increase, respectively. Together with a dramatic increase in circulating ACE levels, these findings argue in favor of deletion of transmembrane anchor, leading to direct secretion of ACE out of cells.ConclusionsWe describe a novel mutation of the ACE gene associated with a major familial elevation of circulating ACE, without evidence of activation of the renin-angiotensin system, target organ damage or cardiovascular complications. These data are consistent with the hypothesis that membrane-bound ACE, rather than circulating ACE, is responsible for Angiotensin II generation and its cardiovascular consequences.

Associations of ACE Gene Insertion/Deletion Polymorphism, ACE Activity, and ACE mRNA Expression with Hypertension in a Chinese Population

“…Persu et al confirmed the hypothesis that membrane-bound ACE, instead of circulating ACE, was responsible for Angiotensin II generation and its cardiovascular consequences [21]. However, several reports suggested that the plasma ACE activity might be higher in adults with several cardiovascular disorders such as myocardial infarction, diabetic nephropathy, and carotid artery thickening [22-24].…”

A Novel Angiotensin I-Converting Enzyme Mutation (S333W) Impairs N-Domain Enzymatic Cleavage of the Anti-Fibrotic Peptide, AcSDKP

“…In contrast, other ACE mutations abolish transmembrane anchoring to cell membrane resulting in direct ACE secretion into the blood, i.e. W1197X [13], IVS25+1G>A [14]. Finally, yet other ACE mutations such as transport – defective ACE mutation - Q1069R [15] and likely many others [16] impaired trafficking to the cell surface and caused renal tubular dysgenesis due to almost complete absence of catalytically ACE on the cell surface.…”

Correlation of angiotensin I-converting enzyme gene insertion/deletion polymorphism with rheumatic heart disease: a meta-analysis

“…ACE gene polymorphism might in cis influence the serum ACE level, and affect the expression of the ACE mRNA [ 47 ]. For example, the ACE IVS25+1G>A variant was shown to be associated with a major familial elevation of circulating ACE [ 48 ]; the deleted form of the ACE I/D variant (D allele) was associated with higher circulating and tissue ACE activity [ 49 ]. In addition, ACE I/D polymorphism was significantly related with serum ACE activity, and male subjects with DD genotype had higher serum ACE activity than female subjects with DD genotype in elderly Chinese [ 50 ].…”