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Functions of Human RGS2 Missense Mutations in Hypertension
Author(s) -
Phan Hoa,
SjÖgren Benita,
Neubig Richard
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.1190.13
Subject(s) - rgs2 , missense mutation , mutant , hek 293 cells , wild type , zebrafish , phenotype , biology , mutation , genetics , g protein , microbiology and biotechnology , medicine , gene , signal transduction , gtpase activating protein
RGS2 attenuates Gq/11 a signaling which mediates the action of a majority of vasoconstrictors. The association between RGS2 deficiency and hypertension has been demonstrated by genetic knock‐out mouse models and RGS2 mutations identified in Japanese hypertensive patients. Though biochemical functions of RGS2 are well characterized, the actual role of RGS2 in human hypertension is not known. 1.6% of individuals from the NHLBI exome sequencing project have missense mutations in RGS2, however, the functional significance of these mutations is unknown. The objective of this study is to examine the effect of human RGS2 missense mutations on protein expression levels, subcellular localization and how they differ from wild‐type RGS2 in their ability to regulate GPCR‐mediated signaling. Wild‐type and 14 RGS2 mutants were investigated by transient transfection in HEK293T and CHO cells. RGS2 A4V showed reduced protein expression (30% of WT, n=10, p<0.01) and impaired inhibition of AT1R‐mediated calcium release (57% of WT vs 23% of A4V, n=5, p<0.01). In contrast, RGS2 Q2L showed reduced expression (40% of WT, n=10, p<0.05) but did not exhibit a significant loss of function (57% of WT vs 51% of Q2L, n=5). In this functional model, RGS2 R44H did not exhibit loss of function as previously reported. Preliminary data on other mutants suggesting functional deficits are currently being assessed as are potential differences in actions of RGS2 mutants on different GPCRs. Together, these studies will provide a molecular understanding of a number of human RGS2 mutant alleles in vitro. This will identify key candidate alleles for further study as contributors to human hypertension. Support or Funding Information Supported by AHA predoctoral fellowship to H.P. and NIH R01GM110195 to R.R.N.