Hemizygosity at the NCF1 Gene in Patients with Williams-Beuren Syndrome Decreases Their Risk of Hypertension

Overview

Journal Am J Hum Genet

Publisher Cell Press

Specialty Genetics

Date 2006 Mar 15

PMID 16532385

Citations 45

Authors

Miguel Del Campo

Anna Antonell

Luis F Magano

Francisco J Munoz

Raquel Flores

Monica Bayes

Luis A Perez Jurado

Affiliations

Soon will be listed here.

Abstract

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 approximately 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 p47(phox) subunit of the NADPH oxidase. Decreased p47(phox) 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.

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References

Bayes M, Magano L, Rivera N, Flores R, Perez Jurado L . Mutational mechanisms of Williams-Beuren syndrome deletions. Am J Hum Genet. 2003; 73(1):131-51. PMC: 1180575. DOI: 10.1086/376565. View

Perez Jurado A . Williams-Beuren syndrome: a model of recurrent genomic mutation. Horm Res. 2003; 59 Suppl 1:106-13. DOI: 10.1159/000067836. View

Ungvari Z, Csiszar A, Huang A, Kaminski P, Wolin M, Koller A . High pressure induces superoxide production in isolated arteries via protein kinase C-dependent activation of NAD(P)H oxidase. Circulation. 2003; 108(10):1253-8. DOI: 10.1161/01.CIR.0000079165.84309.4D. View

Tassabehji M . Williams-Beuren syndrome: a challenge for genotype-phenotype correlations. Hum Mol Genet. 2003; 12 Spec No 2:R229-37. DOI: 10.1093/hmg/ddg299. View

Morris C, Mervis C, Hobart H, Gregg R, Bertrand J, Ensing G . GTF2I hemizygosity implicated in mental retardation in Williams syndrome: genotype-phenotype analysis of five families with deletions in the Williams syndrome region. Am J Med Genet A. 2003; 123A(1):45-59. DOI: 10.1002/ajmg.a.20496. View

Faury G, Pezet M, Knutsen R, Boyle W, Heximer S, E McLean S . Developmental adaptation of the mouse cardiovascular system to elastin haploinsufficiency. J Clin Invest. 2003; 112(9):1419-28. PMC: 228452. DOI: 10.1172/JCI19028. View

Tipney H, Hinsley T, Brass A, Metcalfe K, Donnai D, Tassabehji M . Isolation and characterisation of GTF2IRD2, a novel fusion gene and member of the TFII-I family of transcription factors, deleted in Williams-Beuren syndrome. Eur J Hum Genet. 2004; 12(7):551-60. DOI: 10.1038/sj.ejhg.5201174. View

Touyz R . Reactive oxygen species, vascular oxidative stress, and redox signaling in hypertension: what is the clinical significance?. Hypertension. 2004; 44(3):248-52. DOI: 10.1161/01.HYP.0000138070.47616.9d. View

Wollack J, Kaifer M, LaMonte M, Rothman M . Stroke in Williams syndrome. Stroke. 1996; 27(1):143-6. DOI: 10.1161/01.str.27.1.143. View

10.

Perez Jurado L, Peoples R, Kaplan P, Hamel B, Francke U . Molecular definition of the chromosome 7 deletion in Williams syndrome and parent-of-origin effects on growth. Am J Hum Genet. 1996; 59(4):781-92. PMC: 1914804. View

11.

Bird L, Billman G, Lacro R, Spicer R, Jariwala L, Hoyme H . Sudden death in Williams syndrome: report of ten cases. J Pediatr. 1996; 129(6):926-31. DOI: 10.1016/s0022-3476(96)70042-2. View

12.

Gorlach A, Lee P, Roesler J, Hopkins P, Christensen B, Green E . A p47-phox pseudogene carries the most common mutation causing p47-phox- deficient chronic granulomatous disease. J Clin Invest. 1997; 100(8):1907-18. PMC: 508379. DOI: 10.1172/JCI119721. View

13.

Perez Jurado L, Wang Y, Peoples R, Coloma A, Cruces J, Francke U . A duplicated gene in the breakpoint regions of the 7q11.23 Williams-Beuren syndrome deletion encodes the initiator binding protein TFII-I and BAP-135, a phosphorylation target of BTK. Hum Mol Genet. 1998; 7(3):325-34. DOI: 10.1093/hmg/7.3.325. View

14.

Li D, Faury G, Taylor D, Davis E, Boyle W, Mecham R . Novel arterial pathology in mice and humans hemizygous for elastin. J Clin Invest. 1998; 102(10):1783-7. PMC: 509127. DOI: 10.1172/JCI4487. View

15.

Partsch C, Dreyer G, Gosch A, Winter M, Schneppenheim R, Wessel A . Longitudinal evaluation of growth, puberty, and bone maturation in children with Williams syndrome. J Pediatr. 1999; 134(1):82-9. DOI: 10.1016/s0022-3476(99)70376-8. View

16.

Masia R, Pena A, Marrugat J, Sala J, Vila J, Pavesi M . High prevalence of cardiovascular risk factors in Gerona, Spain, a province with low myocardial infarction incidence. REGICOR Investigators. J Epidemiol Community Health. 1999; 52(11):707-15. PMC: 1756647. DOI: 10.1136/jech.52.11.707. View

17.

Wang M, Schinzel A, Kotzot D, Balmer D, Casey R, Chodirker B . Molecular and clinical correlation study of Williams-Beuren syndrome: No evidence of molecular factors in the deletion region or imprinting affecting clinical outcome. Am J Med Genet. 1999; 86(1):34-43. View

18.

Francke U . Williams-Beuren syndrome: genes and mechanisms. Hum Mol Genet. 1999; 8(10):1947-54. DOI: 10.1093/hmg/8.10.1947. View

19.

Cherniske E, Carpenter T, Klaiman C, Young E, Bregman J, Insogna K . Multisystem study of 20 older adults with Williams syndrome. Am J Med Genet A. 2004; 131(3):255-64. DOI: 10.1002/ajmg.a.30400. View

20.

Kearney P, Whelton M, Reynolds K, Muntner P, Whelton P, He J . Global burden of hypertension: analysis of worldwide data. Lancet. 2005; 365(9455):217-23. DOI: 10.1016/S0140-6736(05)17741-1. View