Mutations in myosin light chain kinase cause familial aortic dissections.
Mutations in smooth muscle cell (SMC)-specific isoforms of α-actin and β-myosin heavy chain, two major components of the SMC contractile unit, cause familial thoracic aortic aneurysms leading to acute aortic dissections (FTAAD). To investigate whether mutations in the kinase that controls SMC contractile function (myosin light chain kinase [MYLK]) cause FTAAD, we sequenced MYLK by using DNA from 193 affected probands from unrelated FTAAD families. One nonsense and four missense variants were identified in MYLK and were not present in matched controls. Two variants, p.R1480X (c.4438C>T) and p.S1759P (c.5275T>C), segregated with aortic dissections in two families with a maximum LOD score of 2.1, providing evidence of linkage of these rare variants to the disease (p = 0.0009). Both families demonstrated a similar phenotype characterized by presentation with an acute aortic dissection with little to no enlargement of the aorta. The p.R1480X mutation leads to a truncated protein lacking the kinase and calmodulin binding domains, and p.S1759P alters amino acids in the α-helix of the calmodulin binding sequence, which disrupts kinase binding to calmodulin and reduces kinase activity in vitro. Furthermore, mice with SMC-specific knockdown of Mylk demonstrate altered gene expression and pathology consistent with medial degeneration of the aorta. Thus, genetic and functional studies support the conclusion that heterozygous loss-of-function mutations in MYLK are associated with aortic dissections.
Department of Internal Medicine, University of Texas Medical School at Houston, TX 77030, USA.
Li
L
Wang
Dong-chuan
DC
Guo
Jiumei
J
Cao
Limin
L
Gong
Kristine E
KE
Kamm
Ellen
E
Regalado
Li
L
Li
Sanjay
S
Shete
Wei-Qi
WQ
He
Min-Sheng
MS
Zhu
Stephan
S
Offermanns
Dawna
D
Gilchrist
John
J
Elefteriades
James T
JT
Stull
Dianna M
DM
Milewicz
D000293:Adolescent; D000328:Adult; D000784:Aortic Dissection / Q000235:genetics*; D000818:Animals; D017545:Aortic Aneurysm, Thoracic / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006801:Humans; D008297:Male; D051379:Mice; D008875:Middle Aged; D009154:Mutation; D009219:Myosin-Light-Chain Kinase / Q000235:genetics*; D010375:Pedigree
D009219:Myosin-Light-Chain Kinase