Dataset Information

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

ABSTRACT: 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.

SUBMITTER: Wallace SE

PROVIDER: S-EPMC6400320 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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

Wallace Stephanie E SE Regalado Ellen S ES Gong Limin L Janda Alexandra L AL Guo Dong-Chuan DC Russo Claudio F CF Kulmacz Richard J RJ Hanna Nadine N Jondeau Guillaume G Boileau Catherine C Arnaud Pauline P Lee Kwanghyuk K Leal Suzanne M SM Hannuksela Matias M Carlberg Bo B Johnston Tami T Antolik Christian C Hostetler Ellen M EM Colombo Roberto R Milewicz Dianna M DM

Genetics in medicine : official journal of the American College of Medical Genetics 20180620 1

<h4>Purpose</h4>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.<h4>Methods</h4>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.<h4>Results</h4>Twenty-three individuals (39%) experi ...[more]

PMID: 29925964

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Project description:Missense variants are present amongst the healthy population, but some of them are causative of human diseases. A classification of variants associated with "healthy" or "diseased" states is therefore not always straightforward. A deeper understanding of the nature of missense variants in health and disease, the cellular processes they may affect, and the general molecular principles which underlie these differences is essential to offer mechanistic explanations of the true impact of pathogenic variants. Here, we have formalised a statistical framework which enables robust probabilistic quantification of variant enrichment across full-length proteins, their domains, and 3D structure-defined regions. Using this framework, we validate and extend previously reported trends of variant enrichment in different protein structural regions (surface/core/interface). By examining the association of variant enrichment with available functional pathways and transcriptomic and proteomic (protein half-life, thermal stability, abundance) data, we have mined a rich set of molecular features which distinguish between pathogenic and population variants: Pathogenic variants mainly affect proteins involved in cell proliferation and nucleotide processing and are enriched in more abundant proteins. Additionally, rare population variants display features closer to common than pathogenic variants. We validate the association between these molecular features and variant pathogenicity by comparing against existing in silico variant impact annotations. This study provides molecular details into how different proteins exhibit resilience and/or sensitivity towards missense variants and provides the rationale to prioritise variant-enriched proteins and protein domains for therapeutic targeting and development. The ZoomVar database, which we created for this study, is available at fraternalilab.kcl.ac.uk/ZoomVar. It allows users to programmatically annotate missense variants with protein structural information and to calculate variant enrichment in different protein structural regions.

Dataset Information

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

Publications

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

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