Recurrent gain-of-function mutation in PRKG1 causes thoracic aortic aneurysms and acute aortic dissections

Dong Chuan Guo; Ellen Regalado; Darren E. Casteel; Regie L. Santos-Cortez; Limin Gong; Jeong Joo Kim; Sarah Dyack; S. Gabrielle Horne; Guijuan Chang; Guillaume Jondeau; Catherine Boileau; Joseph S. Coselli; Zhenyu Li; Suzanne M. Leal; Jay Shendure; Mark J. Rieder; Michael J. Bamshad; Deborah A. Nickerson; Choel Kim; Dianna M. Milewicz

doi:10.1016/j.ajhg.2013.06.019

Recurrent gain-of-function mutation in PRKG1 causes thoracic aortic aneurysms and acute aortic dissections

Dong Chuan Guo, Ellen Regalado, Darren E. Casteel, Regie L. Santos-Cortez, Limin Gong, Jeong Joo Kim, Sarah Dyack, S. Gabrielle Horne, Guijuan Chang, Guillaume Jondeau, Catherine Boileau, Joseph S. Coselli, Zhenyu Li, Suzanne M. Leal, Jay Shendure, Mark J. Rieder, Michael J. Bamshad, Deborah A. Nickerson, Choel Kim, Dianna M. Milewicz

Internal Medicine

Research output: Contribution to journal › Article › peer-review

191 Scopus citations

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.

Original language	English
Pages (from-to)	398-404
Number of pages	7
Journal	American Journal of Human Genetics
Volume	93
Issue number	2
DOIs	https://doi.org/10.1016/j.ajhg.2013.06.019
State	Published - Aug 8 2013

Bibliographical note

Funding Information:
The authors are extremely grateful to the families involved in this study, as well as the physicians and genetic counselors who aided in the collection of clinical data from the families (available in the Supplemental Data ). We would like to thank the National Heart, Lung, and Blood Grand Opportunity Exome Sequencing Project and its ongoing studies, which produced and provided exome variant calls for comparison: the Lung Cohorts Sequencing Project (HL-102923), the Women’s Health Initiative Sequencing Project (HL-102924), the Heart Cohorts Sequencing Project (HL-103010), the Broad Institute Sequencing Project (HL-102925), the GenTAC Registry Consortium (HHSN268200648199C and HHSN268201000048C), the Northwest Genomics Center Sequencing Project (HL-102926, D.A.N, M.J.R, and J.S.), and the Family Studies Project Team. We thank Z. Ren for technical assistance. The following sources provided funding for these studies: RO1 HL62594 (D.M.M.), P50HL083794-01 (D.M.M.), P01HL110869-01 (D.M.M.), UL1 RR024148 (University of Texas Health Science Center at Houston), the Vivian L. Smith Foundation (D.M.M.), the TexGen Foundation (D.M.M.), Richard T. Pisani funds (D.M.M.), RO1 GM090161 (C.K.), Groupements d’Intérêt Scientifique Maladies Rares (C.B.), PHRC AOM09093 (G.J.), PHRC AOM 10108 (C.B.), ANR 2010 BLAN 1129 from the French National Research Agency (G.J.), and the European Union 7 th Framework Program integrated project “Fighting Aneurysmal Disease” ( www.fighting-aneurysm.org ) (J.B.M.).

Funding

The authors are extremely grateful to the families involved in this study, as well as the physicians and genetic counselors who aided in the collection of clinical data from the families (available in the Supplemental Data ). We would like to thank the National Heart, Lung, and Blood Grand Opportunity Exome Sequencing Project and its ongoing studies, which produced and provided exome variant calls for comparison: the Lung Cohorts Sequencing Project (HL-102923), the Women’s Health Initiative Sequencing Project (HL-102924), the Heart Cohorts Sequencing Project (HL-103010), the Broad Institute Sequencing Project (HL-102925), the GenTAC Registry Consortium (HHSN268200648199C and HHSN268201000048C), the Northwest Genomics Center Sequencing Project (HL-102926, D.A.N, M.J.R, and J.S.), and the Family Studies Project Team. We thank Z. Ren for technical assistance. The following sources provided funding for these studies: RO1 HL62594 (D.M.M.), P50HL083794-01 (D.M.M.), P01HL110869-01 (D.M.M.), UL1 RR024148 (University of Texas Health Science Center at Houston), the Vivian L. Smith Foundation (D.M.M.), the TexGen Foundation (D.M.M.), Richard T. Pisani funds (D.M.M.), RO1 GM090161 (C.K.), Groupements d’Intérêt Scientifique Maladies Rares (C.B.), PHRC AOM09093 (G.J.), PHRC AOM 10108 (C.B.), ANR 2010 BLAN 1129 from the French National Research Agency (G.J.), and the European Union 7 th Framework Program integrated project “Fighting Aneurysmal Disease” ( www.fighting-aneurysm.org ) (J.B.M.).

Funders	Funder number
PHRC	AOM 10108, AOM09093
TexGen Foundation	RO1 GM090161
The University of Texas Health Science Center at San Antonio
Vivian L. Smith Foundation
Agence Nationale de la Recherche	2010 BLAN 1129
Agence Nationale de la Recherche

ASJC Scopus subject areas

Genetics
Genetics(clinical)

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10.1016/j.ajhg.2013.06.019

Cite this

Guo, D. C., Regalado, E., Casteel, D. E., Santos-Cortez, R. L., Gong, L., Kim, J. J., Dyack, S., Horne, S. G., Chang, G., Jondeau, G., Boileau, C., Coselli, J. S., Li, Z., Leal, S. M., Shendure, J., Rieder, M. J., Bamshad, M. J., Nickerson, D. A., Kim, C., & Milewicz, D. M. (2013). Recurrent gain-of-function mutation in PRKG1 causes thoracic aortic aneurysms and acute aortic dissections. American Journal of Human Genetics, 93(2), 398-404. https://doi.org/10.1016/j.ajhg.2013.06.019

@article{05b554b8d4f64d5c918bc81fa0d50e45,

title = "Recurrent gain-of-function mutation in PRKG1 causes thoracic aortic aneurysms and acute aortic dissections",

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.",

author = "Guo, {Dong Chuan} and Ellen Regalado and Casteel, {Darren E.} and Santos-Cortez, {Regie L.} and Limin Gong and Kim, {Jeong Joo} and Sarah Dyack and Horne, {S. Gabrielle} and Guijuan Chang and Guillaume Jondeau and Catherine Boileau and Coselli, {Joseph S.} and Zhenyu Li and Leal, {Suzanne M.} and Jay Shendure and Rieder, {Mark J.} and Bamshad, {Michael J.} and Nickerson, {Deborah A.} and Choel Kim and Milewicz, {Dianna M.}",

note = "Funding Information: The authors are extremely grateful to the families involved in this study, as well as the physicians and genetic counselors who aided in the collection of clinical data from the families (available in the Supplemental Data ). We would like to thank the National Heart, Lung, and Blood Grand Opportunity Exome Sequencing Project and its ongoing studies, which produced and provided exome variant calls for comparison: the Lung Cohorts Sequencing Project (HL-102923), the Women{\textquoteright}s Health Initiative Sequencing Project (HL-102924), the Heart Cohorts Sequencing Project (HL-103010), the Broad Institute Sequencing Project (HL-102925), the GenTAC Registry Consortium (HHSN268200648199C and HHSN268201000048C), the Northwest Genomics Center Sequencing Project (HL-102926, D.A.N, M.J.R, and J.S.), and the Family Studies Project Team. We thank Z. Ren for technical assistance. The following sources provided funding for these studies: RO1 HL62594 (D.M.M.), P50HL083794-01 (D.M.M.), P01HL110869-01 (D.M.M.), UL1 RR024148 (University of Texas Health Science Center at Houston), the Vivian L. Smith Foundation (D.M.M.), the TexGen Foundation (D.M.M.), Richard T. Pisani funds (D.M.M.), RO1 GM090161 (C.K.), Groupements d{\textquoteright}Int{\'e}r{\^e}t Scientifique Maladies Rares (C.B.), PHRC AOM09093 (G.J.), PHRC AOM 10108 (C.B.), ANR 2010 BLAN 1129 from the French National Research Agency (G.J.), and the European Union 7 th Framework Program integrated project “Fighting Aneurysmal Disease” ( www.fighting-aneurysm.org ) (J.B.M.). ",

year = "2013",

month = aug,

day = "8",

doi = "10.1016/j.ajhg.2013.06.019",

language = "English",

volume = "93",

pages = "398--404",

number = "2",

}

Guo, DC, Regalado, E, Casteel, DE, Santos-Cortez, RL, Gong, L, Kim, JJ, Dyack, S, Horne, SG, Chang, G, Jondeau, G, Boileau, C, Coselli, JS, Li, Z, Leal, SM, Shendure, J, Rieder, MJ, Bamshad, MJ, Nickerson, DA, Kim, C & Milewicz, DM 2013, 'Recurrent gain-of-function mutation in PRKG1 causes thoracic aortic aneurysms and acute aortic dissections', American Journal of Human Genetics, vol. 93, no. 2, pp. 398-404. https://doi.org/10.1016/j.ajhg.2013.06.019

TY - JOUR

T1 - Recurrent gain-of-function mutation in PRKG1 causes thoracic aortic aneurysms and acute aortic dissections

AU - Guo, Dong Chuan

AU - Regalado, Ellen

AU - Casteel, Darren E.

AU - Santos-Cortez, Regie L.

AU - Gong, Limin

AU - Kim, Jeong Joo

AU - Dyack, Sarah

AU - Horne, S. Gabrielle

AU - Chang, Guijuan

AU - Jondeau, Guillaume

AU - Boileau, Catherine

AU - Coselli, Joseph S.

AU - Li, Zhenyu

AU - Leal, Suzanne M.

AU - Shendure, Jay

AU - Rieder, Mark J.

AU - Bamshad, Michael J.

AU - Nickerson, Deborah A.

AU - Kim, Choel

AU - Milewicz, Dianna M.

N1 - Funding Information: The authors are extremely grateful to the families involved in this study, as well as the physicians and genetic counselors who aided in the collection of clinical data from the families (available in the Supplemental Data ). We would like to thank the National Heart, Lung, and Blood Grand Opportunity Exome Sequencing Project and its ongoing studies, which produced and provided exome variant calls for comparison: the Lung Cohorts Sequencing Project (HL-102923), the Women’s Health Initiative Sequencing Project (HL-102924), the Heart Cohorts Sequencing Project (HL-103010), the Broad Institute Sequencing Project (HL-102925), the GenTAC Registry Consortium (HHSN268200648199C and HHSN268201000048C), the Northwest Genomics Center Sequencing Project (HL-102926, D.A.N, M.J.R, and J.S.), and the Family Studies Project Team. We thank Z. Ren for technical assistance. The following sources provided funding for these studies: RO1 HL62594 (D.M.M.), P50HL083794-01 (D.M.M.), P01HL110869-01 (D.M.M.), UL1 RR024148 (University of Texas Health Science Center at Houston), the Vivian L. Smith Foundation (D.M.M.), the TexGen Foundation (D.M.M.), Richard T. Pisani funds (D.M.M.), RO1 GM090161 (C.K.), Groupements d’Intérêt Scientifique Maladies Rares (C.B.), PHRC AOM09093 (G.J.), PHRC AOM 10108 (C.B.), ANR 2010 BLAN 1129 from the French National Research Agency (G.J.), and the European Union 7 th Framework Program integrated project “Fighting Aneurysmal Disease” ( www.fighting-aneurysm.org ) (J.B.M.).

PY - 2013/8/8

Y1 - 2013/8/8

N2 - 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.

AB - 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.

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Recurrent gain-of-function mutation in PRKG1 causes thoracic aortic aneurysms and acute aortic dissections

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Bibliographical note

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ASJC Scopus subject areas

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