Increased incidence of germline <i>PIEZO1</i> mutations in individuals with idiopathic erythrocytosis

Filser, Mathilde; Giansily‐Blaizot, Muriel; Grenier, Mélanie; Alonso, David Monedero; Bouyer, Guillaume; Pérès, Laurent; Egée, Stéphane; Aral, Bernard; Airaud, Fabrice; Costa, Lydie Da; Picard, Véronique; Cougoul, P.; Palach, Marlène; Bézieau, Stéphane; Garrec, Céline; Martínez, Patricia; Gardie, Betty; Girodon, François

doi:10.1182/blood.2020008424

Cited by 22 publications

(28 citation statements)

References 18 publications

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“…In patients with clinical suspicion of hereditary erythrocytosis, aberrant functioning of proteins involved in the oxygen-sensing pathway (PHD2-HIF2A-VHL-EPO) and erythropoiesis have a high likelihood of being implicated, hence expanded gene/exome sequencing should be offered if available on a research basis in order to uncover novel variants/polymorphisms [ 7 ]. Recently, pathogenic mutations in the PIEZO1 gene were noted in up to 4% of individuals with idiopathic erythrocytosis, in association with clinical or biological manifestations of hereditary xerocytosis (HX)(iron overload, splenomegaly, hemolysis, decreased venous p50) [ 93 ]. In a large series of patients with HX and PIEZO1 mutations, 68% were not anemic; moreover, 7 adults had Hgb >16 g/dl, with two patients known to have erythrocytosis [ 94 ].…”

Section: Diagnostic Approachmentioning

confidence: 99%

JAK2 unmutated erythrocytosis: current diagnostic approach and therapeutic views

et al. 2021

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JAK2 unmutated or non-polycythemia vera (PV) erythrocytosis encompasses both hereditary and acquired conditions. A systematic diagnostic approach begins with documentation of historical hematocrit (Hct)/hemoglobin (Hgb) measurements and classification of the process as life-long/unknown duration or acquired. Further investigation in both categories is facilitated by determination of serum erythropoietin level (EPO). Workup for hereditary/congenital erythrocytosis requires documentation of family history and laboratory screening for high-oxygen affinity hemoglobin variants, 2, 3 biphosphoglycerate deficiency, and germline mutations that are known to alter cellular oxygen sensing (e.g., PHD2, HIF2A, VHL) or EPO signaling (e.g., EPOR mutations); the latter is uniquely associated with subnormal EPO. Acquired erythrocytosis is often elicited by central or peripheral hypoxia resulting from cardiopulmonary disease/high-altitude dwelling or renal artery stenosis, respectively; EPO in the former instance is often normal (compensated by negative feed-back). Other conditions associated with acquired erythrocytosis include EPO-producing tumors and the use of drugs that promote erythropoiesis (e.g., testosterone, erythropoiesis stimulating agents). “Idiopathic erythrocytosis” loosely refers to an otherwise not explained situation. Historically, management of non-PV erythrocytosis has been conflicted by unfounded concerns regarding thrombosis risk, stemming from limited phenotypic characterization, save for Chuvash polycythemia, well-known for its thrombotic tendency. In general, cytoreductive therapy should be avoided and phlebotomy is seldom warranted where frequency is determined by symptom control rather than Hct threshold. Although not supported by hard evidence, cardiovascular risk optimization and low-dose aspirin use are often advised. Application of modern genetic tests and development of controlled therapeutic intervention trials are needed to advance current clinical practice.

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Section: Diagnostic Approachmentioning

confidence: 99%

JAK2 unmutated erythrocytosis: current diagnostic approach and therapeutic views

et al. 2021

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“…Next we used carbonyl cyanide m ‐chlorophenylhydrazone (CCCP), a protonophore that allows monitoring of membrane potential of RBCs via extracellular pH measurement 10 . We recently used this method to describe channel activity on RBCs either with KCNN4 or Piezo1 variants 5,11 . The results unveil differences in cation channel activity of control and patient RBCs (detailed description in the Data S1).…”

Section: Figurementioning

confidence: 99%

Characterisation of Asp669Tyr Piezo1 cation channel activity in red blood cells: an unexpected phenotype

et al. 2021

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“…Indeed, a minority of patients even refer for polycythemia, which was noted in 8% of DHS1 patients recently reported by our group 28 . Recent reports have also described pathogenic gain‐of‐function mutations of PIEZO1 in unexplained polycythemia 78,79 . Kiger et al studied 10 HX patients from eight families, including eight patients carrying a PIEZO1 mutation, using a metabolomic approach 80 .…”

Section: Erythroid Cell Defects In Piezo1‐hxmentioning

confidence: 86%

Recent advances in the pathophysiology of PIEZO1‐related hereditary xerocytosis

et al. 2021

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Hereditary xerocytosis is a rare red blood cell disease related to gain-of-function mutations in the FAM38A gene, encoding PIEZO1, in 90% of cases; PIEZO1 is a broadly expressed mechano-transducer that plays a major role in many cell systems and tissues that respond to mechanical stress. In erythrocytes, PIEZO1 adapts the intracellular ionic content and cell hydration status to the mechanical constraints induced by the environment. Until recently, the pathophysiology of hereditary xerocytosis was mainly believed to be based on the "PIEZO1-Gardos channel axis" in erythrocytes, according to which PIEZO1-activating mutations induce a calcium influx that secondarily activates the Gardos channel, leading to potassium and water efflux and subsequently to red blood cell dehydration. However, recent studies have demonstrated additional roles for PIEZO1 during early erythropoiesis and reticulocyte maturation, as well as roles in other tissues and cells such as lymphatic vessels, hepatocytes, macrophages and platelets that may affect the pathophysiology of the disease. These findings, presented and discussed in this review, broaden our understanding of hereditary xerocytosis beyond that of primarily being a red blood cell disease and identify potential therapeutic targets. | INTRODUCTIONThe PIEZO proteins are a family of mechano-transducers first described in a neuron derived cell line in 2010. 1 The two members are PIEZO1, encoded by FAM38A on chromosome 16, and PIEZO2, encoded by FAM38B on chromosome 18. They are expressed in many tissues. 1,2 The structure of PIEZO1 has been recently elucidated. A first description of the murine protein revealed its three-dimensional structure, consisting of a three-bladed homotrimeric transmembrane helix completed by an extracellular cap. An intra-cytoplasmic domain, split into three parts, called "beams," extends from the transmembrane domain. The C-terminal end of each monomer has an extracellular domain (ECD), which forms the cap, and an intracellular domain (CTD), which appears to be connected to the paddles by the beams and closes the inner ion pore (Figure 1). The assembly provides a hydrophilic central transmembrane duct bordered by six helices that allows the passage of ions. Thus PIEZO1 constitutes a mechanosensitive ion channel due to the flexibility of the three blades. 1 Deformation of the plasma membrane subsequent to mechanical stimulation induces rotation of the PIEZO1 blades, transmitting such deformation to the ECD and CTD domains, allowing the ion channel to open using a lever-like mechanism. 2 When a compressive force is applied parallel to the axis of the ion channel, it induces lateral membrane tension, resulting in flattening and widening of PIEZO1, which causes the pore to open and allows the passage of ions. Such deformations are reversible, and PIEZO1 returns rapidly to its original conformation. [3][4][5] After opening, PIEZO1 acts as a passive channel for mono/divalent cations depending on their extracellular-intracellular Nicolas Jankovsky and Alexis Caulier...

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Increased incidence of germline PIEZO1 mutations in individuals with idiopathic erythrocytosis

Abstract: xerocytosis red cell metabolome shows impaired glycolysis and increased hemoglobin oxygen affinity. Blood Advances.

Cited by 22 publications

References 18 publications

JAK2 unmutated erythrocytosis: current diagnostic approach and therapeutic views

JAK2 unmutated erythrocytosis: current diagnostic approach and therapeutic views

Characterisation of Asp669Tyr Piezo1 cation channel activity in red blood cells: an unexpected phenotype

Recent advances in the pathophysiology of PIEZO1‐related hereditary xerocytosis

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