Angiotensin I-converting enzyme mutation (Trp1197Stop) causes a dramatic increase in blood ACE

Andrew B. Nesterovitch, Kyle D. Hogarth, Vyacheslav A. Adarichev, Elena I. Vinokour, David E. Schwartz, Julian Solway, Sergei M. Danilov

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

Background: Angiotensin-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 Findings: We 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/Significance: We 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.

Original languageEnglish
Article numbere8282
JournalPLoS One
Volume4
Issue number12
DOIs
Publication statusPublished - 2009
Externally publishedYes

Fingerprint

peptidyl-dipeptidase A
Peptidyl-Dipeptidase A
Blood
mutation
Mutation
blood
Terminator Codon
blood serum
Alleles
Pressure regulation
alleles
Gaucher Disease
mutants
Pulmonary diseases
stop codon
Secretory Pathway
Blood pressure
asthma
African Americans
Cell membranes

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Nesterovitch, A. B., Hogarth, K. D., Adarichev, V. A., Vinokour, E. I., Schwartz, D. E., Solway, J., & Danilov, S. M. (2009). Angiotensin I-converting enzyme mutation (Trp1197Stop) causes a dramatic increase in blood ACE. PLoS One, 4(12), [e8282]. https://doi.org/10.1371/journal.pone.0008282

Angiotensin I-converting enzyme mutation (Trp1197Stop) causes a dramatic increase in blood ACE. / Nesterovitch, Andrew B.; Hogarth, Kyle D.; Adarichev, Vyacheslav A.; Vinokour, Elena I.; Schwartz, David E.; Solway, Julian; Danilov, Sergei M.

In: PLoS One, Vol. 4, No. 12, e8282, 2009.

Research output: Contribution to journalArticle

Nesterovitch, AB, Hogarth, KD, Adarichev, VA, Vinokour, EI, Schwartz, DE, Solway, J & Danilov, SM 2009, 'Angiotensin I-converting enzyme mutation (Trp1197Stop) causes a dramatic increase in blood ACE', PLoS One, vol. 4, no. 12, e8282. https://doi.org/10.1371/journal.pone.0008282
Nesterovitch AB, Hogarth KD, Adarichev VA, Vinokour EI, Schwartz DE, Solway J et al. Angiotensin I-converting enzyme mutation (Trp1197Stop) causes a dramatic increase in blood ACE. PLoS One. 2009;4(12). e8282. https://doi.org/10.1371/journal.pone.0008282
Nesterovitch, Andrew B. ; Hogarth, Kyle D. ; Adarichev, Vyacheslav A. ; Vinokour, Elena I. ; Schwartz, David E. ; Solway, Julian ; Danilov, Sergei M. / Angiotensin I-converting enzyme mutation (Trp1197Stop) causes a dramatic increase in blood ACE. In: PLoS One. 2009 ; Vol. 4, No. 12.
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