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

Juliette Albuisson, Swetha E Murthy, Michael Bandell, Bertrand Coste, Hélène Louis-dit-Picard, Jayanti Mathur, Madeleine Fénéant-Thibault, Gérard Tertian, Jean-Pierre de Jaureguiberry, Pierre-Yves Syfuss, Stuart Cahalan, Loic Garçon, Fabienne Toutain, Pierre Simon Rohrlich, Jean Delaunay, Véronique Picard, Xavier Jeunemaitre () and Ardem Patapoutian ()
Additional contact information
Juliette Albuisson: INSERM, UMRS-970, PARCC
Swetha E Murthy: Dorris Neuroscience Center, The Scripps Research Institute
Michael Bandell: Genomics Institute of the Novartis Research Foundation
Bertrand Coste: Dorris Neuroscience Center, The Scripps Research Institute
Hélène Louis-dit-Picard: INSERM, UMRS-970, PARCC
Jayanti Mathur: Genomics Institute of the Novartis Research Foundation
Madeleine Fénéant-Thibault: AP-HP, Service de Biochimie, Hôpital Bicêtre, Le Kremlin Bicêtre 94275, France
Gérard Tertian: Univ Paris-Sud, EA 4531, Chatenay Malabry and Le Kremlin Bicêtre 92296, France
Jean-Pierre de Jaureguiberry: Service de médecine interne, HIA Sainte-Anne, boulevard Sainte-Anne
Pierre-Yves Syfuss: Service de Médecine Interne, Centre Hospitalier
Stuart Cahalan: Dorris Neuroscience Center, The Scripps Research Institute
Loic Garçon: AP-HP, Service d'Hématologie et Immunologie biologiques, Hôpital Saint Antoine
Fabienne Toutain: Service d'Hématologie Oncologie Pédiatrique, Université de Rennes-I, CHU de Rennes, Rennes 35033, France
Pierre Simon Rohrlich: Service d'Hématologie-Oncologie Pédiatrique, CHU, Hôpital Jean Minjoz
Jean Delaunay: AP-HP, Service d'Hématologie et Immunologie, Hôpital Bicêtre, Le Kremlin Bicêtre 94275, France
Véronique Picard: Univ Paris-Sud, EA 4531, Chatenay Malabry and Le Kremlin Bicêtre 92296, France
Xavier Jeunemaitre: INSERM, UMRS-970, PARCC
Ardem Patapoutian: Dorris Neuroscience Center, The Scripps Research Institute

Nature Communications, 2013, vol. 4, issue 1, 1-9

Abstract: Abstract 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.

Date: 2013
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DOI: 10.1038/ncomms2899

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