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Recurrent Gain-of-Function Mutation in PRKG1 Causes Thoracic Aortic Aneurysms and Acute Aortic Dissections

Published on Aug 1, 2013in American Journal of Human Genetics9.92
· DOI :10.1016/j.ajhg.2013.06.019
Dongchuan Guo32
Estimated H-index: 32
(University of Texas Health Science Center at Houston),
Ellen S. Regalado24
Estimated H-index: 24
(University of Texas Health Science Center at Houston)
+ 17 AuthorsDianna M. Milewicz56
Estimated H-index: 56
(University of Texas Health Science Center at Houston)
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Abstract
Gene mutations that lead to decreased contraction of vascular smooth-muscle cells (SMCs) can cause inherited thoracic aortic aneurysms and dissections. Exome sequencing of distant relatives affected by thoracic aortic disease and subsequent Sanger sequencing of additional probands with familial thoracic aortic disease identified the same rare variant, PRKG1 c.530G>A (p.Arg177Gln), in four families. This mutation segregated with aortic disease in these families with a combined two-point LOD score of 7.88. The majority of affected individuals presented with acute aortic dissections (63%) at relatively young ages (mean 31 years, range 17–51 years). PRKG1 encodes type I cGMP-dependent protein kinase (PKG-1), which is activated upon binding of cGMP and controls SMC relaxation. Although the p.Arg177Gln alteration disrupts binding to the high-affinity cGMP binding site within the regulatory domain, the altered PKG-1 is constitutively active even in the absence of cGMP. The increased PKG-1 activity leads to decreased phosphorylation of the myosin regulatory light chain in fibroblasts and is predicted to cause decreased contraction of vascular SMCs. Thus, identification of a gain-of-function mutation in PRKG1 as a cause of thoracic aortic disease provides further evidence that proper SMC contractile function is critical for maintaining the integrity of the thoracic aorta throughout a lifetime.
  • References (21)
  • Citations (99)
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References21
Newest
#1Ellen S. Regalado (University of Texas Health Science Center at Houston)H-Index: 24
#2Dongchuan Guo (University of Texas Health Science Center at Houston)H-Index: 32
Last.Suzanne M. Leal (BCM: Baylor College of Medicine)H-Index: 54
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#1Jeong Joo Kim (BCM: Baylor College of Medicine)H-Index: 5
#2Darren E. Casteel (UCSD: University of California, San Diego)H-Index: 20
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#1Ingrid van de Laar (EUR: Erasmus University Rotterdam)H-Index: 15
#2Rogier A. Oldenburg (EUR: Erasmus University Rotterdam)H-Index: 26
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#1Sakiko Inamoto (University of Texas Health Science Center at Houston)H-Index: 1
#2Callie S. Kwartler (University of Texas Health Science Center at Houston)H-Index: 11
Last.Mark C. Hannibal (UW: University of Washington)H-Index: 20
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#1Li Wang (University of Texas Health Science Center at Houston)H-Index: 1
#2Dongchuan Guo (University of Texas Health Science Center at Houston)H-Index: 32
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#1Sharron H. Francis (Vandy: Vanderbilt University)H-Index: 50
#2Jennifer L. Busch (Vandy: Vanderbilt University)H-Index: 6
Last.Jackie D. Corbin (Vandy: Vanderbilt University)H-Index: 62
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#1Dianna M. Milewicz (University of Texas at Austin)H-Index: 56
#2Dongchuan Guo (University of Texas at Austin)H-Index: 32
Last.Hariyadarshi Pannu (University of Texas at Austin)H-Index: 18
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#1Dongchuan Guo (University of Texas Health Science Center at Houston)H-Index: 32
#2Hariyadarshi Pannu (University of Texas Health Science Center at Houston)H-Index: 18
Last.Dianna M. Milewicz (University of Texas Health Science Center at Houston)H-Index: 56
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#1Sherene Shalhub (UW: University of Washington)H-Index: 13
#2Ellen S. Regalado (University of Texas Health Science Center at Houston)H-Index: 24
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#1Norifumi Takeda (UTokyo: University of Tokyo)H-Index: 13
#2Norifumi Takeda (UTokyo: University of Tokyo)H-Index: 9
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