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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
- Source :
- PLoS One, 8, 4, PLoS ONE, Vol 8, Iss 4, p e59537 (2013), PLoS ONE, PLoS One, 8, PLoS One (print), 8(4). Public Library of Science, PLoS One, Vol. 8, no. 4, p. e59537 (2013)
- Publication Year :
- 2013
-
Abstract
- Contains fulltext : 116540.pdf (Publisher’s version ) (Open Access) 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. METHODS AND 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. 12 p.
- Subjects :
- Male
Anatomy and Physiology
Captopril
Gene Expression
Angiotensin-Converting Enzyme Inhibitors
Blood Pressure
medicine.disease_cause
Cardiovascular
Cardiovascular System
Biochemistry
Renin-Angiotensin System
Nucleic Acids
Gene expression
Pathology
Sequence Deletion
Mutation
Multidisciplinary
Splice site mutation
biology
Cardiovascular diseases [NCEBP 14]
Middle Aged
Enzymes
Pedigree
Hypertension
Medicine
Female
medicine.drug
Research Article
Adult
medicine.medical_specialty
Heterozygote
Adolescent
Science
Molecular Sequence Data
Peptidyl-Dipeptidase A
Genetic Mutation
Vascular Biology
Diagnostic Medicine
Internal medicine
Renin–angiotensin system
medicine
Genetics
Humans
Genetic Testing
Biology
Aged
Base Sequence
Proteins
Angiotensin-converting enzyme
Heterozygote advantage
Human Genetics
Dendritic Cells
Angiotensin II
Hormones
Transmembrane Proteins
Endocrinology
Asymptomatic Diseases
biology.protein
RNA
Biomarkers
General Pathology
Subjects
Details
- ISSN :
- 19326203
- Volume :
- 8
- Database :
- OpenAIRE
- Journal :
- PLoS One
- Accession number :
- edsair.doi.dedup.....bb5a2846e786f519e7315a4f420a9e94