Impaired PIEZO1 function in patients with a novel autosomal recessive congenital lymphatic dysplasia

Lukacs, Viktor; Mathur, Jayanti; Mao, Rong; Bayrak-Toydemir, Pınar; Procter, Melinda; Cahalan, Stuart M.; Kim, Helen J.; Bandell, Michael; Longo, Nicola; Day, Ronald W.; Stevenson, David A.; Patapoutian, Ardem; Krock, Bryan L.

doi:10.1038/ncomms9329

Cited by 247 publications

(240 citation statements)

References 34 publications

(48 reference statements)

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“…In humans, gain-of-function (GOF) mutations in Piezo1 are linked to dehydrated hereditary stomatocytosis (DHS) 9–12 , a disease in which red blood cells are dehydrated and have increased permeability to cations, and GOF Piezo2 mutations are associated with distal arthrogryposis 13 . Loss-of-function (LOF) mutations in Piezo1 and Piezo2 are linked to congenital lymphatic dysplasia 14 and defective touch perception and proprioception 15–17 , respectively. Piezos are structurally unrelated to other proteins, and are uniquely large compared to other ion channels (>2000 amino acids).…”

Section: Introductionmentioning

confidence: 99%

Structure of the mechanically activated ion channel Piezo1

Saotome

Murthy

Kefauver

et al. 2017

Nature

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423

382

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Summary Piezo1 and Piezo2 are mechanically activated ion channels that mediate touch perception, proprioception, and vascular development. Piezos are distinct from other ion channels and their structure remains poorly defined, impeding detailed study of their gating and ion permeation properties. Here, we report a high-resolution cryo-electron microscopy structure of the mouse Piezo1 trimer. The detergent-solubilized complex adopts a three-blade propeller shape with a curved transmembrane region containing at least 26 transmembrane helices per protomer. The flexible propeller blades can adopt distinct conformations, and consist of a series of four-transmembrane helix bundles we term ‘Piezo Repeats’. Carboxy-terminal domains line the central ion pore, and the channel is closed by constrictions in the cytosol. A kinked helical beam and anchor domain link the Piezo Repeats to the pore, and are poised to allosterically control gating. The structure provides a springboard to further dissect how Piezos are regulated by mechanical force.

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Section: Introductionmentioning

confidence: 99%

Structure of the mechanically activated ion channel Piezo1

Saotome

Murthy

Kefauver

et al. 2017

Nature

Self Cite

423

382

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“…Defects in PIEZO1 function are likely to cause alterations in vascular development and regulation, including arterial hypertension. In fact, biallelic mutations in PIEZO1 resulting in attenuated PIEZO1 function have recently been described in patients with congenital lymphatic dysplasia (50). It will be interesting to analyze the function and structure of PIEZO1 in various forms of arterial hypertension.…”

Section: +mentioning

confidence: 99%

Endothelial cation channel PIEZO1 controls blood pressure by mediating flow-induced ATP release

Wang

Chennupati

Kaur

et al. 2016

Journal of Clinical Investigation

412

411

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“…Ion channels Mutations in the mechanically activated ion channel PIEZO1 are associated with human lymphedema (Fotiou et al 2015;Lukacs et al 2015). Hence, PIEZO1 and its paralog, PIEZO2, might be involved in sensing OSS.…”

Section: Sensing Ossmentioning

confidence: 99%

Mechanotransduction activates canonical Wnt/β-catenin signaling to promote lymphatic vascular patterning and the development of lymphatic and lymphovenous valves

et al. 2016

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Lymphatic vasculature regulates fluid homeostasis by returning interstitial fluid to blood circulation. Lymphatic endothelial cells (LECs) are the building blocks of the entire lymphatic vasculature. LECs originate as a homogeneous population of cells predominantly from the embryonic veins and undergo stepwise morphogenesis to become the lymphatic capillaries, collecting vessels or valves. The molecular mechanisms underlying the morphogenesis of the lymphatic vasculature remain to be fully understood. Here we show that canonical Wnt/β-catenin signaling is necessary for lymphatic vascular morphogenesis. Lymphatic vascular-specific ablation of β-catenin in mice prevents the formation of lymphatic and lymphovenous valves. Additionally, lymphatic vessel patterning is defective in these mice, with abnormal recruitment of mural cells. We found that oscillatory shear stress (OSS), which promotes lymphatic vessel maturation, triggers Wnt/β-catenin signaling in LECs. In turn, Wnt/β-catenin signaling controls the expression of several molecules, including the lymphedema-associated transcription factor FOXC2. Importantly, FOXC2 completely rescues the lymphatic vessel patterning defects in mice lacking β-catenin. Thus, our work reveals that mechanical stimulation is a critical regulator of lymphatic vascular development via activation of Wnt/β-catenin signaling and, in turn, FOXC2.

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Impaired PIEZO1 function in patients with a novel autosomal recessive congenital lymphatic dysplasia

Cited by 247 publications

References 34 publications

Structure of the mechanically activated ion channel Piezo1

Structure of the mechanically activated ion channel Piezo1

Endothelial cation channel PIEZO1 controls blood pressure by mediating flow-induced ATP release

Mechanotransduction activates canonical Wnt/β-catenin signaling to promote lymphatic vascular patterning and the development of lymphatic and lymphovenous valves

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