title: 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: BACKGROUND
  Angiotensin-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.
  
  
  RESULTS
  Two 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.
  
  
  CONCLUSIONS
  We 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.
authors.affiliation: Pole of Cardiovascular Research, Institut de Recherche Expérimentale et Clinique, Université Catholique de Louvain, Brussels, Belgium. alexandre.persu@uclouvain.be
authors.forename: Alexandre
authors.initials: A
authors.lastname: Persu
authors.forename: Michel
authors.initials: M
authors.lastname: Lambert
authors.forename: Jaap
authors.initials: J
authors.lastname: Deinum
authors.forename: Marta
authors.initials: M
authors.lastname: Cossu
authors.forename: Nathalie
authors.initials: N
authors.lastname: de Visscher
authors.forename: Leonid
authors.initials: L
authors.lastname: Irenge
authors.forename: Jerôme
authors.initials: J
authors.lastname: Ambroise
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Minon
authors.forename: Andrew B
authors.initials: AB
authors.lastname: Nesterovitch
authors.forename: Alexander
authors.initials: A
authors.lastname: Churbanov
authors.forename: Isolda A
authors.initials: IA
authors.lastname: Popova
authors.forename: Sergei M
authors.initials: SM
authors.lastname: Danilov
authors.forename: A H Jan
authors.initials: AH
authors.lastname: Danser
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Gala
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D058070:Asymptomatic Diseases; D001483:Base Sequence; D001794:Blood Pressure / Q000187:drug effects; D002216:Captopril / Q000494:pharmacology; D003713:Dendritic Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D005260:Female; D015870:Gene Expression; D006579:Heterozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D010375:Pedigree; D007703:Peptidyl-Dipeptidase A / Q000097:blood / Q000235:genetics*; D012084:Renin-Angiotensin System / Q000187:drug effects / Q000235:genetics*; D017384:Sequence Deletion
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D002216:Captopril; D007703:Peptidyl-Dipeptidase A
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