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.
Highlights
Angiotensin I-converting enzyme (ACE, CD143) is a Zn2+ carboxydipeptidase which plays key roles in the regulation of blood pressure and in the development of vascular pathology and remodeling [1,2,3]
During determination of Angiotensin-converting enzyme (ACE) activity in 10 volunteers without sarcoidosis, we found one individual with extremely high ACE activity – .13-fold greater than the mean ACE activity in the other volunteers (Fig. 1A)
Based on the immunoprecipitation of ACE by mAb 1B3 (Fig. 1B–D), ACE from subject N1 seems to have a mutation in the stalk region of ACE that is similar, but not identical, to that of individuals having Pro1199Leu mutation
Summary
Angiotensin I-converting enzyme (ACE, CD143) is a Zn2+ carboxydipeptidase which plays key roles in the regulation of blood pressure and in the development of vascular pathology and remodeling [1,2,3]. Serum ACE originates likely from endothelial cells [14] by proteolytic cleavage [15,16]. Angiotensin-converting enzyme (ACE) metabolizes many peptides and plays a key role in blood pressure regulation and vascular remodeling. 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
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