Details

Autor(en) / Beteiligte

• Wang, Ya-Juan
• Tayo, Bamidele O
• Bandyopadhyay, Anupam
• Wang, Heming
• Feng, Tao
• Franceschini, Nora
• Tang, Hua
• Gao, Jianmin
• Sung, Yun Ju
• Elston, Robert C
• Williams, Scott M
• Cooper, Richard S
• Mu, Ting-Wei
• Zhu, Xiaofeng
• Copenhaver, Gregory P.

Titel

The association of the vanin-1 N131S variant with blood pressure is mediated by endoplasmic reticulum-associated degradation and loss of function

Ist Teil von

• PLoS genetics, 2014-09, Vol.10 (9), p.e1004641-e1004641

Ort / Verlag

United States: Public Library of Science

Erscheinungsjahr

2014

Quelle

MEDLINE

Beschreibungen/Notizen

• High blood pressure (BP) is the most common cardiovascular risk factor worldwide and a major contributor to heart disease and stroke. We previously discovered a BP-associated missense SNP (single nucleotide polymorphism)-rs2272996-in the gene encoding vanin-1, a glycosylphosphatidylinositol (GPI)-anchored membrane pantetheinase. In the present study, we first replicated the association of rs2272996 and BP traits with a total sample size of nearly 30,000 individuals from the Continental Origins and Genetic Epidemiology Network (COGENT) of African Americans (P=0.01). This association was further validated using patient plasma samples; we observed that the N131S mutation is associated with significantly lower plasma vanin-1 protein levels. We observed that the N131S vanin-1 is subjected to rapid endoplasmic reticulum-associated degradation (ERAD) as the underlying mechanism for its reduction. Using HEK293 cells stably expressing vanin-1 variants, we showed that N131S vanin-1 was degraded significantly faster than wild type (WT) vanin-1. Consequently, there were only minimal quantities of variant vanin-1 present on the plasma membrane and greatly reduced pantetheinase activity. Application of MG-132, a proteasome inhibitor, resulted in accumulation of ubiquitinated variant protein. A further experiment demonstrated that atenolol and diltiazem, two current drugs for treating hypertension, reduce the vanin-1 protein level. Our study provides strong biological evidence for the association of the identified SNP with BP and suggests that vanin-1 misfolding and degradation are the underlying molecular mechanism.