Heterogeneous phenotype of Hereditary Xerocytosis in association with PIEZO1 variants.

Abstract	Hereditary Xerocytosis (HX) is an autosomal dominantly inherited congenital hemolytic anemia associated with erythrocyte dehydration due to decreased intracellular potassium content resulting in increased mean corpuscular hemoglobin concentration. The affected members of HX families show compensated anemia with splenomegaly, hemosiderosis, and perinatal edema but are in large part transfusion independent. Functional studies show a link between mutations in mechanosensitive ion channel, encoded by PIEZO1 gene and the HX. We identified new PIEZO1 variants that are likely pathogenic in three phenotypically characterized multi-generational HX Brazilian families. Interestingly, one missense variant of the PIEZO1 gene identified, p.E2494V was associated in trans with the previously reported most frequent pathogenic duplication p.E2496ELE. The three-dimensional structure of the human protein modeled using structural coordinates of the mouse Piezo1 solved by cryo-electron microscopy (Cryo-ME) showed that the two identified variants, p.M2007L and p.T2014I, are localized to an important mechanosensitive transmembrane domain suggesting a conformational mechanism for altered channel's gating. The p.E2496ELE variant identified alters the extension of helix α1 bringing it much closer to the beam affecting the position of it structure at the end of the pore.
Authors	Priscila de Meira Oliveira, Andrea Balan, Nair H Muto, Murilo C Cervato, Guilherme H H Fonseca, Liliana M Suganuma, Sandra Gualandro, João R R Pinho, Narla Mohandas, Paulo A A Silveira, Roberta Sitnik
Journal	Blood cells, molecules & diseases (Blood Cells Mol Dis) Vol. 82 Pg. 102413 (05 2020) ISSN: 1096-0961 [Electronic] United States
PMID	32109669 (Publication Type: Journal Article)
Copyright	Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.
Chemical References	Ion Channels PIEZO1 protein, human Piezo1 protein, mouse
Topics	Adolescent Adult Amino Acid Substitution Anemia, Hemolytic, Congenital (genetics) Animals Child Female Humans Hydrops Fetalis (genetics) Infant, Newborn Ion Channels (chemistry, genetics) Male Mice Middle Aged Mutation, Missense Protein Conformation, alpha-Helical Protein Domains

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