Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
, 21 (1), 144-151

MYLK Pathogenic Variants Aortic Disease Presentation, Pregnancy Risk, and Characterization of Pathogenic Missense Variants


MYLK Pathogenic Variants Aortic Disease Presentation, Pregnancy Risk, and Characterization of Pathogenic Missense Variants

Stephanie E Wallace et al. Genet Med.


Purpose: 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.

Methods: 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.

Results: 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.

Conclusion: 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.

Keywords: MYLK; acute aortic dissection; hereditary thoracic aortic disease; myosin light-chain kinase; thoracic aortic surgery.


Figure 1
Figure 1. Pathogenic MYLK variants and segregation of variant p.Tyr1575His in famIT-001
A. A schematic depiction of the long and short form of myosin light chain kinase (MLCK) shows the location of the MYLK pathogenic variants included in these studies. All variants are located in the short form of MLCK, which is the only form expressed in the thoracic aorta. Carriers of the variants depicted here were included in the phenotypic analysis. B. The pedigree depicts a multi-generational family with two distant arms affected with thoracic aortic disease. Church parish records were used to confirm common ancestry. Circles represent females, squares represent males. A line through the individual indicates that they are deceased and the legend provides information about the phenotype associated with shaded symbols. T/C is used to denote the pathogenic variant genotype and T/T is used to denote the WT genotype.
Figure 2
Figure 2. Kaplan Meier Survival Analysis
A. Kaplan Meier failure function evaluating cumulative risk of aortic event in persons with variants in MYLK. Individuals who died suddenly with no prior history of aortic event were not included in the analysis. B. Kaplan Meier curve demonstrating the significant difference in age of onset amongst individuals with missense mutations vs. null variants. Persons with missense variants in MYLK presented approximately 10 years earlier than those with null variants. C. Kaplan Meier failure function evaluating cumulative risk of type A aortic dissection in persons with MYLK variants. D. Kaplan Meier curve demonstrating significant difference in age of onset for type A dissection in individuals with missense versus null variants.
Figure 3
Figure 3. Functional assays of missense variants in MYLK
The kinase activity and CaM activation of recombinant wild-type (WT) and mutant MLCK were assessed, and the results are shown along with previously published data on a variant shown to decrease MLCK activity, p.Ser1759Pro. The rate of 32P incorporation into the regulatory light chair (RLC) was measured. The maximal activities of WT MLCK (circle), variant MLCK (square), and Ser1759Pro MLCK (diamond) were obtained at different RLC concentrations. The three variants which were assessed: Tyr1575His (A), Gly1317Cys (B), and Cys1384Gly (C). The relative percentage of maximal kinase activity was plotted as a function of CaM concentration. The data points represented the mean ± standard error of three or more determinations. The data were fit to the Michaelis-Menten equation for estimation of the Vmax values and KCaM value.

Similar articles

See all similar articles

Cited by 4 articles


    1. Guo DC, Pannu H, Papke CL, et al. Mutations in smooth muscle alpha-actin(ACTA2) lead to thoracic aortic aneurysms and dissections. Nat Genet. 2007;39:1488–93. - PubMed
    1. Disabella E, Grasso M, Gambarin FI, et al. Risk of dissection in thoracic aneurysms associated with mutations of smooth muscle alpha-actin 2(ACTA2) Heart. 2011;97(4):321–6. - PubMed
    1. Guo DC, Regalado E, Casteel DE, et al. Recurrent Gain-of-Function Mutation in PRKG1 Causes Thoracic Aortic Aneurysms and Acute Aortic Dissections. Am J Hum Genet. 2013;93:398–404. - PMC - PubMed
    1. Wang L, Guo DC, Cao J, et al. Mutations in Myosin light chain kinase cause familial aortic dissections. Am J Hum Genet. 2010;87:701–7. - PMC - PubMed
    1. Pannu H, Tran-Fadulu V, Papke CL, et al. MYH11 mutations result in a distinct vascular pathology driven by insulin-like growth factor 1 and angiotensin II. Hum Mol Genet. 2007;16:3453–62. - PMC - PubMed

Publication types