Angiotensin I-Converting Enzyme Mutation (Trp1197Stop) Causes a Dramatic Increase in Blood ACE

Abstract

BackgroundAngiotensin-converting enzyme (ACE) metabolizes many peptides and plays a key role in blood pressure regulation and vascular remodeling. Elevated ACE levels may be associated with an increased risk for different cardiovascular or respiratory diseases, including asthma. Previously, a molecular mechanism underlying a 5-fold familial increase of blood ACE was discovered: Pro1199Leu substitution enhanced the cleavage-secretion process. Carriers of this mutation were Caucasians from Europe (mostly Dutch) or had European roots.Methodology/Principal FindingsWe have found a family of African-American descent whose affected members' blood ACE level was increased 13-fold over normal. In affected family members, codon TGG coding for Trp1197 was substituted in one allele by TGA (stop codon). As a result, half of ACE expressed in these individuals had a length of 1196 amino acids and lacked a transmembrane anchor. This ACE mutant is not trafficked to the cell membrane and is directly secreted out of cells; this mechanism apparently accounts for the high serum ACE level seen in affected individuals. A haplotype of the mutant ACE allele was determined based on 12 polymorphisms, which may help to identify other carriers of this mutation. Some but not all carriers of this mutation demonstrated airflow obstruction, and some but not all have hypertension.Conclusions/SignificanceWe have identified a novel Trp1197Stop mutation that results in dramatic elevation of serum ACE. Since blood ACE elevation is often taken as a marker of disease activity (sarcoidosis and Gaucher diseases), it is important for clinicians and medical scientists to be aware of alternative genetic causes of elevated blood ACE that are not apparently linked to disease.

New Perspectives in the Renin-Angiotensin-Aldosterone System (RAAS) III: Endogenous Inhibition of Angiotensin Converting Enzyme (ACE) Provides Protection against Cardiovascular Diseases

“…This mutation affected at least eight families, but there were no ACE-related clinical abnormalities or hypertension. An other mutation that was accompanied by a 13-fold elevation of the serum ACE concentration was also without increased occurrence of cardiovascular disease [53]. Some other mutations of the ACE gene are known to be coupled with a mildly elevated ACE concentration, but again without an enhanced incidence of cardiovascular diseases [54]–[57].…”

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.…”

Multi-Species Comparative Analysis of the Equine ACE Gene Identifies a Highly Conserved Potential Transcription Factor Binding Site in Intron 16

“…Both an animo acid exchange P1199L and the nonsense ACE mutation W1197X dramatically increase circulating ACE levels, with these polymorphisms affecting cleavage of the enzyme from the cell membrane (secretion of the enzyme) and thus circulating ACE levels rather than transcription and membrane bound ACE levels [75], [76]. Other studies have focused on identifying polymorphisms that instead alter gene expression.…”