TY - JOUR
T1 - Dehydrated hereditary stomatocytosis linked to gain-of-function mutations in mechanically activated PIEZO1 ion channels
AU - Albuisson, Juliette
AU - Murthy, Swetha E.
AU - Bandell, Michael
AU - Coste, Bertrand
AU - Louis-Dit-Picard, Hélène
AU - Mathur, Jayanti
AU - Fénéant-Thibault, Madeleine
AU - Tertian, Gérard
AU - De Jaureguiberry, Jean Pierre
AU - Syfuss, Pierre Yves
AU - Cahalan, Stuart
AU - Garçon, Loic
AU - Toutain, Fabienne
AU - Simon Rohrlich, Pierre
AU - Delaunay, Jean
AU - Picard, Véronique
AU - Jeunemaitre, Xavier
AU - Patapoutian, Ardem
PY - 2013
Y1 - 2013
N2 - 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 pathophysioloy.
AB - 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 pathophysioloy.
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U2 - 10.1038/ncomms2899
DO - 10.1038/ncomms2899
M3 - Article
C2 - 23695678
AN - SCOPUS:84878689800
SN - 2041-1723
VL - 4
JO - Nature communications
JF - Nature communications
M1 - 1884
ER -