Recurrent mutation in the <i><scp>PIEZO1</scp></i> gene in two families of hereditary xerocytosis with fetal hydrops

Bénéteau, Claire; Thierry, Gaëlle; Blesson, Sophie; Vaillant, C. Le; Picard, Véronique; Béné, Marie C.; Eveillard, Marion; Caignec, Cédric Le

doi:10.1111/cge.12147

Cited by 29 publications

(28 citation statements)

References 3 publications

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“…The PIEZO1 mutations described until now in DHS1a‐b patients are several. Most of them consist of missense modifications . Although the majority of the mutations are private, three recurrent variants (Leu2495_Glu2496dup, Arg2456His, and Thr2127Met) account for more than 50% of all mutated alleles in DHS1a‐b patients.…”

Section: Molecular Defects Of Hereditary Stomatocytosismentioning

confidence: 95%

“…The identified mutations are mostly missense and mainly located in the highly conserved C‐terminus of the protein (Table b) . Several electrophysiology studies demonstrated that the mutations cause a gain‐of‐function phenotype with delayed inactivation of the channel, suggesting increased cation permeability that leads to DHS erythrocyte dehydration .…”

Section: Hereditary Stomatocytosis: Syndromic and Nonsyndromic Formsmentioning

confidence: 99%

“…To date, 29 independent families (133 affected subjects) related to PIEZO1 mutations (DHS1a‐b) and 6 families (33 affected patients) related to KCNN4 mutations (DHS2) have been described . Thus, 83% of DHS patients carried PIEZO1 mutations.…”

Section: Hereditary Stomatocytosis: Syndromic and Nonsyndromic Formsmentioning

confidence: 99%

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Hereditary stomatocytosis: An underdiagnosed condition

et al. 2017

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Hereditary stomatocytoses are a wide class of hemolytic anemias characterized by alterations of ionic flux with increased cation permeability that results in inappropriate shrinkage or swelling of the erythrocytes, and water lost or gained osmotically. The last few years have been crucial for new acquisitions in this field in terms of identifying new causative genes and of studying their pathogenetic mechanisms. This review summarizes the main features of erythrocyte membrane transport diseases, dividing them into forms with either isolated erythroid phenotype (nonsyndromic) or extra-hematological manifestations (syndromic), and focusing particularly on the most recent advances regarding dehydrated forms of hereditary stomatocytosis and familial pseudohyperkalemia.

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Section: Molecular Defects Of Hereditary Stomatocytosismentioning

confidence: 95%

Section: Hereditary Stomatocytosis: Syndromic and Nonsyndromic Formsmentioning

confidence: 99%

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Hereditary stomatocytosis: An underdiagnosed condition

et al. 2017

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“…The PIEZO1 gene was identified as the causative gene of both the isolated and syndromic forms of DHS . The mutations identified to date are mostly missense . Several electrophysiology studies have demonstrated that pathogenic variants result in a gain‐of‐function phenotype with delayed inactivation of the cation channel, which suggests that the increased cation permeability leads to DHS erythrocyte dehydration .…”

Section: Introductionmentioning

confidence: 99%

Gain‐of‐function mutations in PIEZO1 directly impair hepatic iron metabolism via the inhibition of the BMP/SMADs pathway

et al. 2019

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Dehydrated hereditary stomatocytosis (DHS), or xerocytosis, is an autosomal dominant hemolytic anemia. Most patients with DHS carry mutations in the PIEZO1 gene encoding a mechanosensitive cation channel. We here demonstrate that patients with DHS have low levels of hepcidin and only a slight increase of ERFE, the erythroid negative regulator of hepcidin. We demonstrated that at the physiological level, PIEZO1 activation induced Ca 2+ influx and suppression of HAMP expression in primary hepatocytes. In two hepatic cellular models expressing PIEZO1 WT and two PIEZO1 gain-of-function mutants (R2456H and R2488Q), we highlight altered expression of a few genes/proteins involved in iron metabolism. Mutant cells showed increased intracellular Ca 2+ compared to WT, which was correlated to increased phosphorylation of ERK1/2, inhibition of the BMP-SMADs pathway, and suppression of HAMP transcription. Moreover, the HuH7 cells, treated with PD0325901, a potent inhibitor of ERK1/2 phosphorylation, reduced the phosphorylation of ERK1/2 with the consequent increased phosphorylation of SMAD1/5/8, confirming the link between the two pathways. Another "proof of concept" for the mechanism that links PIEZO1 to HAMP regulation was obtained by mimicking PIEZO1 activation by cell Ca 2+ overload, by the Ca 2+ ionophore A23187. There was strong down-regulation of HAMP gene expression after this Ca 2+ overload. Finally, the inhibition of PIEZO1 by GsMTx4 leads to phenotype rescue. This is the first demonstration of a direct link between PIEZO1 and iron metabolism, which defines the channel as a new hepatic iron metabolism regulator and as a possible therapeutic target of iron overload in DHS and other iron-loading anemias.

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“…Piezo2 functions as a major mechanotransduction channel for sensation of gentle touch (Ikeda et al 2014;Maksimovic et al 2014;Woo et al 2014), proprioception (Woo et al 2015), airway stretch and lung inflation (Nonomura et al 2016). Pathophysiologically, mutations in Piezo1 are associated with dehydrated hereditary stomatocytosis, lymphatic dysplasia, hereditary high phosphatidylcholine haemolytic anaemia and haemochromatosis-induced diabetes mellitus (Zarychanski et al 2012;Albuisson et al 2013, Bae et al 2013Szklarczyk et al 2013;Beneteau et al 2014, Sandberg et al 2014, Andolfo et al 2015Fotiou et al 2015). Mutations in Piezo2 are linked to distal arthrogryposis, Gordon syndrome, Marden-Walker syndrome and scoliosis with peripheral sensory dysfunction McMillin et al 2014;Chesler et al 2016).…”

Section: Introductionmentioning

confidence: 99%

The mechanosensitive Piezo1 channel: structural features and molecular bases underlying its ion permeation and mechanotransduction

Wang

Xiao

2017

The Journal of Physiology

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The evolutionarily conserved Piezo family of proteins, including Piezo1 and Piezo2, encodes the long-sought-after mammalian mechanosensitive cation channels that play critical roles in various mechanotransduction processes such as touch, pain, proprioception, vascular development and blood pressure regulation. Mammalian Piezo proteins contain over 2500 amino acids with numerous predicted transmembrane segments, and do not bear sequence homology with any known class of ion channels. Thus, it is imperative, but challenging, to understand how they serve as effective mechanotransducers for converting mechanical force into electrochemical signals. Here, we review the recent major breakthroughs in determining the three-bladed, propeller-shaped structure of mouse Piezo1 using the state-of-the-art cryo-electron microscopy (cryo-EM) and functionally dissecting out the molecular bases that define its ion permeation and mechanotransduction properties, which provide key insights into clarifying its oligomeric status and pore-forming region. We also discuss the hypothesis that the complex Piezo proteins can be deduced into discrete mechanotransduction and ion-conducting pore modules, which coordinate to fulfil their specialized function in mechanical sensing and transduction, ion permeation and selection.

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Recurrent mutation in the PIEZO1 gene in two families of hereditary xerocytosis with fetal hydrops

Cited by 29 publications

References 3 publications

Hereditary stomatocytosis: An underdiagnosed condition

Hereditary stomatocytosis: An underdiagnosed condition

Gain‐of‐function mutations in PIEZO1 directly impair hepatic iron metabolism via the inhibition of the BMP/SMADs pathway

The mechanosensitive Piezo1 channel: structural features and molecular bases underlying its ion permeation and mechanotransduction

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