TY - JOUR
T1 - Hemizygosity at the NCF1 gene in patients with Williams-Beuren syndrome decreases their risk of hypertension
AU - Del Campo, Miguel
AU - Antonell, Anna
AU - Magano, Luis F.
AU - Muñoz, Francisco J.
AU - Flores, Raquel
AU - Bayés, Mònica
AU - Jurado, Luis A.Pérez
N1 - Funding Information:
We thank Victoria Campuzano for critical reading, Roser Corominas and Mireia Coma for excellent technical assistance, and Mariano Sentí and Jaume Marrugat for providing samples of hypertensive and control individuals. A.A. was supported by the Departament d'Universitats, Recerca i Societat de la Informarció and Generalitat de Catalunya grant FI02-00790. L.F.M. was supported by the Fondo de Investigación Sanitaria, Spanish Ministry of Health grant FPI-99/9083. This work was supported by grants from the Spanish Ministries of Science and Education (SAF2004-6382) and Health (Networks of Cooperative Research grants C03/07, G03/045, and G03/184), Genome Spain (grant JLI/038), and the Fondation Jerôme Lejeune.
PY - 2006/4
Y1 - 2006/4
N2 - Williams-Beuren syndrome (WBS), caused by a heterozygous deletion at 7q11.23, represents a model for studying hypertension, the leading risk factor for mortality worldwide, in a genetically determined disorder. Haploinsufficiency at the elastin gene is known to lead to the vascular stenoses in WBS and is also thought to predispose to hypertension, present in ∼50% of patients. Detailed clinical and molecular characterization of 96 patients with WBS was performed to explore clinical-molecular correlations. Deletion breakpoints were precisely defined and were found to result in variability at two genes, NCF1 and GTF2IRD2. Hypertension was significantly less prevalent in patients with WBS who had the deletion that included NCF1 (P = .02), a gene coding for the p47phox subunit of the NADPH oxidase. Decreased p47phox protein levels, decreased superoxide anion production, and lower protein nitrotyrosination were all observed in cell lines from patients hemizygous at NCF1. Our results indicate that the loss of a functional copy of NCF1 protects a proportion of patients with WBS against hypertension, likely through a lifelong reduced angiotensin II-mediated oxidative stress. Therefore, antioxidant therapy that reduces NADPH oxidase activity might have a potential benefit in identifiable patients with WBS in whom serious complications related to hypertension have been reported, as well as in forms of essential hypertension mediated by a similar pathogenic mechanism.
AB - Williams-Beuren syndrome (WBS), caused by a heterozygous deletion at 7q11.23, represents a model for studying hypertension, the leading risk factor for mortality worldwide, in a genetically determined disorder. Haploinsufficiency at the elastin gene is known to lead to the vascular stenoses in WBS and is also thought to predispose to hypertension, present in ∼50% of patients. Detailed clinical and molecular characterization of 96 patients with WBS was performed to explore clinical-molecular correlations. Deletion breakpoints were precisely defined and were found to result in variability at two genes, NCF1 and GTF2IRD2. Hypertension was significantly less prevalent in patients with WBS who had the deletion that included NCF1 (P = .02), a gene coding for the p47phox subunit of the NADPH oxidase. Decreased p47phox protein levels, decreased superoxide anion production, and lower protein nitrotyrosination were all observed in cell lines from patients hemizygous at NCF1. Our results indicate that the loss of a functional copy of NCF1 protects a proportion of patients with WBS against hypertension, likely through a lifelong reduced angiotensin II-mediated oxidative stress. Therefore, antioxidant therapy that reduces NADPH oxidase activity might have a potential benefit in identifiable patients with WBS in whom serious complications related to hypertension have been reported, as well as in forms of essential hypertension mediated by a similar pathogenic mechanism.
UR - http://www.scopus.com/inward/record.url?scp=33645466249&partnerID=8YFLogxK
U2 - 10.1086/501073
DO - 10.1086/501073
M3 - Article
C2 - 16532385
AN - SCOPUS:33645466249
SN - 0002-9297
VL - 78
SP - 533
EP - 542
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
IS - 4
ER -