Journal Article

Dehydrated hereditary stomatocytosis linked to gain-of-function mutations in mechanically activated PIEZO1 ion channels

Albuisson, Juliette, Syfuss, Pierre-Yves, Bandell, Michael, Louis-dit-Picard, Hélène, Simon Rohrlich, Pierre, Jeunemaitre, Xavier, Coste, Bertrand, Cahalan, Stuart, Murthy, Swetha E, Delaunay, Jean, Garçon, Loic, de Jaureguiberry, Jean-Pierre, Patapoutian, Ardem, Mathur, Jayanti, Tertian, Gérard, Fénéant-Thibault, Madeleine, Toutain, Fabienne, Picard, Véronique

2013

Overview

Dehydrated hereditary stomatocytosis is a genetic condition with defective red blood cell membrane properties that causes an imbalance in intracellular cation concentrations. Recently, two missense mutations in the mechanically activated PIEZO1 ( FAM38A ) ion channel were associated with dehydrated hereditary stomatocytosis. However, it is not known how these mutations affect PIEZO1 function. Here, by combining linkage analysis and whole-exome sequencing in a large pedigree and Sanger sequencing in two additional kindreds and 11 unrelated dehydrated hereditary stomatocytosis cases, we identify three novel missense mutations and one recurrent duplication in PIEZO1 , demonstrating that it is the major gene for dehydrated hereditary stomatocytosis. All the dehydrated hereditary stomatocytosis-associated mutations locate at C-terminal half of PIEZO1. Remarkably, we find that all PIEZO1 mutations give rise to mechanically activated currents that inactivate more slowly than wild-type currents. This gain-of-function PIEZO1 phenotype provides insight that helps to explain the increased permeability of cations in red blood cells of dehydrated hereditary stomatocytosis patients. Our findings also suggest a new role for mechanotransduction in red blood cell biology and pathophysiology. Dehydrated hereditary stomatocytosis is a genetic condition in which the permeability of red blood cells to cations in increased. Albuisson and colleagues find that mutations in the mechanically-activated PIEZO1 ion channel are the major cause of the disease and result in more slowly inactivating currents.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/208/2489/144 / 631/57/2272 / 692/699/1541 / Adolescent / Adult / Aged / Amino Acid Sequence / Anemia, Hemolytic, Congenital - genetics / Biomechanical Phenomena / Cations / Child / DNA Mutational Analysis / Erythrocytes / Female / Genetics / Hematology / Human genetics / Human health and pathology / Humanities and Social Sciences / Humans / Hydrophobic and Hydrophilic Interactions / Hydrops Fetalis - genetics / Ion Channel Gating - genetics / Ion Channels - chemistry / Ion Channels - genetics / Ion Channels - metabolism / Kinetics / Life Sciences / Male / Middle Aged / Molecular Sequence Data / multidisciplinary / Mutation / Mutation - genetics / Pedigree / Recombinant Proteins - metabolism / Science / Science (multidisciplinary) / Young Adult