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

• Published in: Nature communications Vol. 4; no. 1; p. 1884
• Main Authors: Albuisson, Juliette, Murthy, Swetha E, Bandell, Michael, Coste, Bertrand, Louis-dit-Picard, Hélène, Mathur, Jayanti, Fénéant-Thibault, Madeleine, Tertian, Gérard, de Jaureguiberry, Jean-Pierre, Syfuss, Pierre-Yves, Cahalan, Stuart, Garçon, Loic, Toutain, Fabienne, Simon Rohrlich, Pierre, Delaunay, Jean, Picard, Véronique, Jeunemaitre, Xavier, Patapoutian, Ardem
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 2013; Nature Publishing Group
• Subjects: 631/208/2489/144; 631/57/2272; 692/699/1541; Adolescent; Adult; Aged; Amino Acid Sequence; Anemia, Hemolytic, Congenital - genetics; Biomechanical Phenomena; Child; DNA Mutational Analysis; 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 - genetics; Pedigree; Recombinant Proteins - metabolism; Science; Science (multidisciplinary); Young Adult
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms2899

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.