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

Wallace, Stephanie E; Regalado, Ellen S.; Gong, Limin; Janda, Alexandra; Guo, Dongchuan; Russo, Claudio; Kulmacz, Richard J.; Hanna, Nadine; Jondeau, Guillaume; Boileau, Cathérine; Arnaud, Pauline; Lee, Kwanghyuk; Leal, Suzanne M.; Hannuksela, Matias; Carlberg, Bo; Johnston, Tami; Antolik, Christian; Hostetler, Ellen M.; Colombo, Roberto; Milewicz, Dianna M.

doi:10.1038/s41436-018-0038-0

Cited by 43 publications

(40 citation statements)

References 18 publications

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“…TAA-causing mutations are also found in genes involved in the regulation of myosin-dependent contraction [ 87 ]. TAA-associated mutations in MYLK, which codes for MLCK, reduce its kinase activity and thus impair contraction and promote relaxation [ 219 , 297 , 298 , 299 ]. Similarly, one recurring TAA-associated gain-of-function mutation (pR177Q) in PRKG1 , which codes for type I cGMP-dependent protein kinase (PKG-1), results in the constitutive activation of PKG-1, a cGMP-activated enzyme that promotes relaxation by phosphorylating and activating MLCP [ 87 , 220 ].…”

Section: Genes Associated With Syndromic and Non-syndromic Hereditmentioning

confidence: 99%

“…In this model, mutations in components of matrix proteins or enzymes necessary for their assembly/maturation would initiate disease by directly compromising the function of elastic fibers or other ECM structures to which integrins connect, whereas mutations in components and regulators of the actin–myosin cytoskeleton would do so by perturbing tension and/or myosin-dependent maturation of focal adhesions [ 62 , 141 , 217 , 218 , 219 , 239 , 261 , 294 , 295 , 296 , 297 , 298 , 299 ].…”

Section: Proposed Model Of Taa Pathogenesis Based On the Function mentioning

confidence: 99%

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Insights on the Pathogenesis of Aneurysm through the Study of Hereditary Aortopathies

Creamer

Bramel

MacFarlane

2021

Genes

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Thoracic aortic aneurysms (TAA) are permanent and localized dilations of the aorta that predispose patients to a life-threatening risk of aortic dissection or rupture. The identification of pathogenic variants that cause hereditary forms of TAA has delineated fundamental molecular processes required to maintain aortic homeostasis. Vascular smooth muscle cells (VSMCs) elaborate and remodel the extracellular matrix (ECM) in response to mechanical and biochemical cues from their environment. Causal variants for hereditary forms of aneurysm compromise the function of gene products involved in the transmission or interpretation of these signals, initiating processes that eventually lead to degeneration and mechanical failure of the vessel. These include mutations that interfere with transduction of stimuli from the matrix to the actin–myosin cytoskeleton through integrins, and those that impair signaling pathways activated by transforming growth factor-β (TGF-β). In this review, we summarize the features of the healthy aortic wall, the major pathways involved in the modulation of VSMC phenotypes, and the basic molecular functions impaired by TAA-associated mutations. We also discuss how the heterogeneity and balance of adaptive and maladaptive responses to the initial genetic insult might contribute to disease.

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Section: Genes Associated With Syndromic and Non-syndromic Hereditmentioning

confidence: 99%

Section: Proposed Model Of Taa Pathogenesis Based On the Function mentioning

confidence: 99%

Insights on the Pathogenesis of Aneurysm through the Study of Hereditary Aortopathies

Creamer

Bramel

MacFarlane

2021

Genes

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“…Hopefully, global collaborative efforts, like the recently revived GenTAC Alliance, will help move with the standardization. In addition, patient support organizations, like the Marfan Foundation, and John Ritter Foundation, and international patient registries, like the Montalcino Aortic Consortium 95–97 and BAV (bicuspid aortic valve) Consortium, 11,98 are poised to approach individuals with thoracic aortic disease for further clinical trials to prevent or delay disease progression.…”

Section: Closing Remarks and Future Perspectivesmentioning

confidence: 99%

Therapies for Thoracic Aortic Aneurysms and Acute Aortic Dissections

Milewicz

Ramirez

2019

ATVB

Self Cite

103

109

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Thoracic aortic aneurysms that progress to acute aortic dissections are often fatal. Thoracic aneurysms have been managed with treatment with β-adrenergic blocking agents (β-blockers) and routine surveillance imaging, followed by surgical repair of the aneurysm when the risk of dissection exceeds the risk for repair. Thus, there is a window to initiate therapies to slow aortic enlargement and delay or ideally negate the need for surgical repair of the aneurysm to prevent a dissection. Mouse models of Marfan syndrome—a monogenic disorder predisposing to thoracic aortic disease—have been used extensively to identify such therapies. The initial fi that TGFβ (transformation growth factor-β) signaling was increased in the aortic media of a Marfan syndrome mouse model and that its inhibition via TGFβ neutralization or At1r (Ang II [angiotensin II] type I receptor) antagonism prevented aneurysm development was generally viewed as a groundbreaking discovery that could be translated into the first cure of thoracic aortic disease. However, several large randomized trials of pediatric and adult patients with Marfan syndrome have subsequently yielded no evidence that At1r antagonism by losartan slows aortic enlargement more effectively than conventional treatment with β-blockers. Subsequent studies in mouse models have begun to resolve the complex molecular pathophysiology underlying onset and progression of aortic disease and have emphasized the need to preserve TGFβ signaling to prevent aneurysm formation. This review describes critical experiments that have influenced the evolution of our understanding of thoracic aortic disease, in addition to discussing old controversies and identifying new therapeutic opportunities.

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“…Gao et al speculated that MYLK was a candidate gene engaged in acute lung injury susceptibility and disease [ 30 ]. Another study showed that the thoracic aortic disease phenotype was associated with MYLK pathogenic variants [ 31 ]. Recently, Dai et al reported the higher expression of circular RNA (circRNA) MYLK in human prostate cancer tissue and suggested using circRNA-MYLK as a tool to diagnose and determine treatments for prostate cancer [ 32 ].…”

Section: Discussionmentioning

confidence: 99%

MYLK and PTGS1 Genetic Variations Associated with Osteoporosis and Benign Breast Tumors in Korean Women

Cho

Jin

Eom

2021

Genes

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Osteoporosis, characterized by reduced bone mass and increased bone fragility, is a disease prevalent in women. Likewise, breast cancer is a multifactorial disease and considered the major cause of mortality in premenopausal and postmenopausal women worldwide. Our data demonstrated the association of the MYLK gene and PTGS1 gene variants with osteoporosis and benign breast tumor risk and the impact of ovariectomy on osteoporosis in Korean women. We performed a genome-wide association study (GWAS) of women with osteoporosis and benign breast tumors. There were 60 single nucleotide polymorphisms (SNPs) and 12 SNPs in the MYLK and PTGS1 genes, associated with benign breast tumors and osteoporosis. Our study showed that women with homozygous MYLK rs12163585 major alleles had an increased risk of osteoporosis following ovariectomy compared to those with minor alleles. Women carrying the minor PTGS1 rs1213265 allele and not treated via ovariectomy carried a higher risk of osteoporosis than those who underwent ovariectomy with a homozygous genotype at the major alleles. Our results suggest that both the MYLK and PTGS1 genes are genetic factors associated with the phenotypes, and these associations appear to be modulated by ovariectomy.

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

Abstract: 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.

Cited by 43 publications

References 18 publications

Insights on the Pathogenesis of Aneurysm through the Study of Hereditary Aortopathies

Insights on the Pathogenesis of Aneurysm through the Study of Hereditary Aortopathies

Therapies for Thoracic Aortic Aneurysms and Acute Aortic Dissections

MYLK and PTGS1 Genetic Variations Associated with Osteoporosis and Benign Breast Tumors in Korean Women

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