Abstract 219: Early-onset Cerebrovascular Disease and Smooth Muscle Dysfunction Associated with a Novel Mylk1 Mutation

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Introduction: Genetic arteriopathies are an important cause of early-onset cerebrovascular disease. We report a novel mutation in the gene for myosin light chain kinase 1 (Mylk1), a protein essential for smooth muscle contractility, leading to vascular smooth muscle dysfunction and stroke. Our patient presented with signs of systemic smooth muscle dysfunction at birth, and developed left hemiparesis due to right MCA stroke at 8 months of age. Cerebral angiogram showed tortuous intracranial vessels with right M1 occlusion and extensive proliferative ICA collaterals.

Methods: Whole exome sequencing showed a de novo mutation in Mylk1 leading to a P1588L substitution in the ATP binding site. To understand the effect of this substitution on protein function, we built a homology model of MYLK1 based on the resolved crystal structure of MYLK4. We then investigated conformational changes in the secondary structure using Molecular Dynamics Simulation. The protein was solvated in TIP3P water and simulated at 310K, at 1 bar, in 150 mmol/L of NaCl. The integrity of the model was verified by Ramachandran plot, with 99.6% of the amino acids in allowed regions.

Results: The P1588L substitution alters the loop-helix structure of the ATP binding domain, which is integral for the catalytic activity of MYLK1. The substitution also affects the polarity and the flexibility of the ATP binding site, which is likely to affect the docking and binding of ATP.

Conclusions: Using in silico modeling, we demonstrated that a novel mutation in Mylk1 alters protein structure, likely interfering with systemic and vascular smooth muscle contractility and resulting in a clinical phenotype of stroke in childhood.

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