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

Am J Hum Genet. 2013 Aug 8;93(2):398-404. doi: 10.1016/j.ajhg.2013.06.019. Epub 2013 Aug 1.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Disease
  • Adolescent
  • Adult
  • Amino Acid Sequence
  • Aneurysm, Dissecting / enzymology
  • Aneurysm, Dissecting / genetics*
  • Aneurysm, Dissecting / physiopathology
  • Aorta, Thoracic / enzymology*
  • Aorta, Thoracic / physiopathology
  • Aortic Aneurysm, Thoracic / enzymology
  • Aortic Aneurysm, Thoracic / genetics*
  • Aortic Aneurysm, Thoracic / physiopathology
  • Cyclic GMP / metabolism
  • Cyclic GMP-Dependent Protein Kinase Type I / genetics*
  • Cyclic GMP-Dependent Protein Kinase Type I / metabolism
  • Exome
  • Female
  • Fibroblasts / enzymology
  • Fibroblasts / pathology
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Male
  • Middle Aged
  • Molecular Sequence Data
  • Muscle Contraction
  • Muscle, Smooth, Vascular / enzymology*
  • Muscle, Smooth, Vascular / physiopathology
  • Mutation*
  • Myosin Light Chains / genetics
  • Myosin Light Chains / metabolism
  • Pedigree

Substances

  • Myosin Light Chains
  • Cyclic GMP-Dependent Protein Kinase Type I
  • PRKG1 protein, human
  • Cyclic GMP