Dehydrated Hereditary Stomatocytosislinked to gain-of-function mutations in mechanically activated PIEZO1 ion channels

• Published in: Nature communications 2013-01, Vol.4, p.1884-1884
• 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, Rohrlich, Pierre Simon, Delaunay, Jean, Picard, Véronique, Jeunemaitre, Xavier, Patapoutian, Ardem
• Format: Article
• Language: English
• ISSN: 2041-1723
• DOI: 10.1038/ncomms2899

Dehydrated hereditary stomatocytosis (DHS) is a genetic condition with defective red blood cell (RBC) membrane properties that causes an imbalance in intracellular cation concentrations. Recently, two missense mutations inthe mechanically activated PIEZO1 (FAM38A) ion channel were associated with DHS. 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 DHS cases, we identifythree novel missense mutations and one recurrent duplication in PIEZO1 , demonstrating that it is the major gene for DHS. All the DHS-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 RBCs of DHS patients. Our findings also suggest a new role for mechanotransduction in RBC biology and pathophysiology.