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MYLK pathogenic variants aortic disease presentation, pregnancy risk, and characterization of pathogenic missense variants

Published on Jan 1, 2019in Genetics in Medicine 8.68
· DOI :10.1038/s41436-018-0038-0
Stephanie Wallace3
Estimated H-index: 3
(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
Heritable thoracic aortic disease can result from null variants in MYLK, which encodes myosin light-chain kinase (MLCK). Data on which MYLK missense variants are pathogenic and information to guide aortic disease management are limited. Clinical data from 60 cases with MYLK pathogenic variants were analyzed (five null and two missense variants), and the effect of missense variants on kinase activity was assessed. Twenty-three individuals (39%) experienced an aortic event (defined as aneurysm repair or dissection); the majority of these events (87%) were aortic dissections. Aortic diameters were minimally enlarged at the time of dissection in many cases. Time-to-aortic-event curves showed that missense pathogenic variant (PV) carriers have earlier-onset aortic events than null PV carriers. An MYLK missense variant segregated with aortic disease over five generations but decreases MYLK kinase acitivity marginally. Functional Assays fail to identify all pathogenic variants in MYLK. These data further define the aortic phenotype associated with MYLK pathogenic variants. Given minimal aortic enlargement before dissection, an alternative approach to guide the timing of aortic repair is proposed based on the probability of a dissection at a given age.
  • References (18)
  • Citations (3)
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References18
Newest
Published on Feb 1, 2018in Pulmonary circulation 2.08
Ting Wang18
Estimated H-index: 18
(UA: University of Arizona),
Mary E. Brown19
Estimated H-index: 19
(UIC: University of Illinois at Chicago)
+ 5 AuthorsJoe G. N. Garcia87
Estimated H-index: 87
(UA: University of Arizona)
Sphingosine 1-phosphate (S1P) is a potent bioactive endogenous lipid that signals a rearrangement of the actin cytoskeleton via the regulation of non-muscle myosin light chain kinase isoform (nmMLCK). S1P induces critical nmMLCK Y464 and Y471 phosphorylation resulting in translocation of nmMLCK to the periphery where spatially-directed increases in myosin light chain (MLC) phosphorylation and tension result in lamellipodia protrusion, increased cell-cell adhesion, and enhanced vascular barrier i...
Published on Oct 1, 2017in Clinical Genetics 4.10
Ilse Luyckx4
Estimated H-index: 4
(University of Antwerp),
Dorien Proost4
Estimated H-index: 4
(University of Antwerp)
+ 9 AuthorsAline Verstraeten11
Estimated H-index: 11
(University of Antwerp)
Published on Dec 1, 2016in BMC Medical Genetics 1.74
Matias Hannuksela3
Estimated H-index: 3
(Umeå University),
Eva-Lena Stattin17
Estimated H-index: 17
(Umeå University)
+ 4 AuthorsBo Carlberg28
Estimated H-index: 28
(Umeå University)
Background: Mutations in MYLK cause non- syndromic familial thoracic aortic aneurysms and dissections (FTAAD). Very little is known about the phenotype of affected families. We sought to characteri ...
Published on Dec 1, 2016in Circulation-cardiovascular Genetics 4.86
Guillaume Jondeau51
Estimated H-index: 51
(University of Paris),
Jacques Ropers4
Estimated H-index: 4
+ 25 AuthorsCécile Zordan1
Estimated H-index: 1
Background: The natural history of aortic diseases in patients with TGFBR1 or TGFBR2 mutations reported by different investigators has varied greatly. In particular, the current recommendations for the timing of surgical repair of the aortic root aneurysms may be overly aggressive. Methods and Results: The Montalcino Aortic Consortium, which includes 15 centers worldwide that specialize in heritable thoracic aortic diseases, was used to gather data on 441 patients from 228 families, with 176 cas...
Published on Nov 1, 2015in The Annals of Thoracic Surgery 3.92
Bulat A. Ziganshin14
Estimated H-index: 14
(Yale University),
Allison E. Bailey1
Estimated H-index: 1
(Yale University)
+ 7 AuthorsJohn A. Elefteriades54
Estimated H-index: 54
(Yale University)
Background Hereditary factors play an important etiologic role in thoracic aortic aneurysm and dissection (TAAD), with a number of genes proven to predispose to this condition. We initiated a clinical program for routine genetic testing of individuals for TAAD by whole exome sequencing (WES). Here we present our initial results. Methods The WES was performed in 102 patients (mean age 56.8 years; range 13 to 83; 70 males [68.6%]) with TAAD. The following 21-gene panel was tested by WES: ACTA2, AD...
Published on Jul 1, 2014in Annals of cardiothoracic surgery
Akshar Y. Patel2
Estimated H-index: 2
(UM: University of Michigan),
Kim A. Eagle114
Estimated H-index: 114
,
Prashant Vaishnava7
Estimated H-index: 7
Acute type B aortic dissection comprises approximately one-third of all aortic dissection cases. Although this catastrophic cardiovascular condition was first described in the medical literature over two centuries ago, data on the optimal diagnostic and treatment modalities for type B dissection was slow to evolve throughout the latter half of the twentieth century, even as newer diagnostic techniques and management strategies became commonplace. To further elucidate contemporary practice patter...
Published on Apr 1, 2014in Journal of the American College of Cardiology 18.64
Bartosz Rylski17
Estimated H-index: 17
(University of Freiburg),
Philipp Blanke37
Estimated H-index: 37
+ 14 AuthorsChristian Schlensak22
Estimated H-index: 22
Objectives The purpose of this study is to delineate changes in aortic geometry and diameter due to dissection. Background Aortic diameter is the major criterion for elective ascending aortic replacement for dilated ascending aortas to prevent aortic dissection. However, recommendations are made on the basis of clinical experience and observation of diameters of previously dissected aortas. Methods Six tertiary centers on 2 continents reviewed their acute aortic dissection type A databases, whic...
Published on Aug 1, 2013in American Journal of Human Genetics 9.92
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 AuthorsGuillaume Jondeau51
Estimated H-index: 51
(University of Paris)
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...
Published on Mar 15, 2013in Journal of Biological Chemistry
Ning Gao4
Estimated H-index: 4
(UTSW: University of Texas Southwestern Medical Center),
Jian Jhang Huang1
Estimated H-index: 1
(UTSW: University of Texas Southwestern Medical Center)
+ 3 AuthorsJames T. Stull65
Estimated H-index: 65
Ca2+/calmodulin-dependent myosin light chain kinase (MLCK) phosphorylates smooth muscle myosin regulatory light chain (RLC) to initiate contraction. We used a tamoxifen-activated, smooth muscle-specific inactivation of MLCK expression in adult mice to determine whether MLCK was differentially limiting in distinct smooth muscles. A 50% decrease in MLCK in urinary bladder smooth muscle had no effect on RLC phosphorylation or on contractile responses, whereas an 80% decrease resulted in only a 20% ...
Published on Aug 1, 2011in Genetics in Medicine 8.68
Dru F. Leistritz10
Estimated H-index: 10
(UW: University of Washington),
Melanie Pepin23
Estimated H-index: 23
(UW: University of Washington)
+ 1 AuthorsPeter H. Byers69
Estimated H-index: 69
(UW: University of Washington)
COL3A1 haploinsufficiency results in a variety of Ehlers-Danlos syndrome type IV with delayed onset of complications and longer life expectancy
Cited By3
Newest
Published on Jun 1, 2019
Brooke N. Wolford4
Estimated H-index: 4
(UM: University of Michigan),
Whitney Hornsby6
Estimated H-index: 6
(UM: University of Michigan)
+ 21 AuthorsEllen M. Schmidt16
Estimated H-index: 16
Background: Thoracic aortic dissection is an emergent life-threatening condition. Routine screening for genetic variants causing thoracic aortic dissection is not currently performed for patients o...
Published on Feb 15, 2019in Circulation Research 15.86
Amélie Pinard1
Estimated H-index: 1
(University of Texas Health Science Center at Houston),
Gregory T. Jones30
Estimated H-index: 30
(University of Otago),
Dianna M. Milewicz56
Estimated H-index: 56
(University of Texas Health Science Center at Houston)
Published on Dec 17, 2018in bioRxiv
Brooke N. Wolford4
Estimated H-index: 4
(UM: University of Michigan),
Whitney Hornsby6
Estimated H-index: 6
(UM: University of Michigan)
+ 21 AuthorsEllen M. Schmidt16
Estimated H-index: 16
Background: Thoracic aortic dissection is an emergent life-threatening condition. Routine screening for genetic variants causing thoracic aortic dissection is not currently performed for patients or their family members. Methods: We performed whole exome sequencing of 240 patients with thoracic aortic dissection (n=235) or rupture (n=5) and 258 controls matched for age, sex, and ancestry. Blinded to case-control status, we annotated variants in 11 genes for pathogenicity. Results: Twenty-four pa...