ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000003.11) (NC_000003.12)
Evidence for haploinsufficiency phenotype
PubMed ID Description
21055718 Wang et al (2010) sequenced the MYLK gene (and other smooth muscle cell genes) in 193 unrelated probands with FTAAD [Familial thoracic aortic aneurisms and dissections] and identified five heterozygous sequence-level mutations (1 nonsense, 4 missense) not present in 188 ethically matched controls. Two variants (c.3637G>A and c.4195G>A) lie outside (N-terminal) to the kinase domain and are not predicted to disrupt kinase activity of MYLK. The nonsense mutation (c.4438C>T) occurs in the kinase domain and is predicted to lead to either nonsense-mediated mRNA decay of the long and short isoform transcripts or a truncated MYLK protein (p.R1480*) missing both the kinase and Calmodulin (CaM) binding domains; functional studies on this variant were not performed. ["The p.R1480X mutation leads to either nonsense-mediated decay of the message or a truncated protein missing the kinase and CaM binding domains and is therefore predicted to disrupt kinase activity but not to disturb telokin expression"] The missense mutations (c.5260G>A and c.5275T>C) occur in the C-terminal CaM domain, were shown by in vitro co-expression and protein pull-down studies to disrupt CaM binding and kinase function, and were thus suggested to lead to a loss of MYLK function. None of these mutations are predicted to disturb expression of telokin protein. Based on functional and segregation (where possible) studies, the authors propose that two of these mutations are causative for FTAAD: c.5275T>C (p.S1759P), which is completely penetrant (LOD 0.3), and the nonsense allele c.4438C>T (p.R1480X), which shows incomplete penetrance (LOD 1.2 or 1.8). Additional studies are needed to support causation for the other three variants.
25907466 Proost et al (2015) developed a next-generation sequencing panel of 14 TAA genes and screened 55 syndromic and nonsyndromic TAA patients. In one patient with non-syndromic TAA, they identified a nonsense mutation c.4459C>T (p.Arg1487*) occurring in the kinase domain of MYLK in a patient with thoracic aortic aneurysm/dissection (TAA). Functional analysis of this variant was not performed.

Haploinsufficiency phenotype comments:

MYLK encodes myosin light chain kinase (MLCK), a ubiquitously expressed calcium/calmodulin dependent enzyme that regulates the activity of myosin regulatory light chains to facilitate myosin interaction with actin filaments to produce contractile activity in smooth muscle cell and nonmuscle tissues. Two protein isoforms (long and short) of MLCK are expressed. This gene also encodes telokin, a small protein identical in sequence to the C-terminus of MLCK, which functions in smooth muscle to stabilize myosin filaments. Mutations in MYLK and other SMC-specific genes (ACTA2, MYH11) have been identified in association with familial thoracic aortic disease, characterized by progressive enlargement of the ascending aorta that predisposes to acute dissections (familial thoracic aortic aneurisms/dissections; FTAAD). This phenotype typically shows autosomal dominant inheritance in families, with incomplete penetrance and variable expressivity. At this time there is limited evidence to support the haploinsufficiency of this gene. Current evidence includes three independent studies that took a candidate gene approach to identifying MYLK mutations in patients affected by TAAD. These studies identified two nonsense mutations predicted to result in loss-of-function through either nonsense-mediated mRNA decay or a truncated MLCK protein that would lack both the kinase and CaM binding domains; however there are no reported functional studies on the nonsense mutations. Functional studies have also suggested that two of the reported missense mutations disrupt CaM binding of MLCK. There are currently no reported whole gene deletions. Due to the limited number of FTAAD-associated mutations in MYLK in the literature, approaches taken to identify these mutations, limited understanding of the functional consequence of these mutations on all MYLK gene products, and demonstration of incomplete penetrance for one nonsense mutation, the current haploinsufficiency score is 1.

  • Triplosensitivity score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity