title: Dehydrated hereditary stomatocytosis linked to gain-of-function mutations in mechanically activated PIEZO1 ion channels.
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.
authors.affiliation: INSERM, UMRS-970, PARCC, Paris 75015, France.
authors.forename: Juliette
authors.initials: J
authors.lastname: Albuisson
authors.forename: Swetha E
authors.initials: SE
authors.lastname: Murthy
authors.forename: Michael
authors.initials: M
authors.lastname: Bandell
authors.forename: Bertrand
authors.initials: B
authors.lastname: Coste
authors.forename: Hélène
authors.initials: H
authors.lastname: Louis-Dit-Picard
authors.forename: Jayanti
authors.initials: J
authors.lastname: Mathur
authors.forename: Madeleine
authors.initials: M
authors.lastname: Fénéant-Thibault
authors.forename: Gérard
authors.initials: G
authors.lastname: Tertian
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: de Jaureguiberry
authors.forename: Pierre-Yves
authors.initials: PY
authors.lastname: Syfuss
authors.forename: Stuart
authors.initials: S
authors.lastname: Cahalan
authors.forename: Loic
authors.initials: L
authors.lastname: Garçon
authors.forename: Fabienne
authors.initials: F
authors.lastname: Toutain
authors.forename: Pierre
authors.initials: P
authors.lastname: Simon Rohrlich
authors.forename: Jean
authors.initials: J
authors.lastname: Delaunay
authors.forename: Véronique
authors.initials: V
authors.lastname: Picard
authors.forename: Xavier
authors.initials: X
authors.lastname: Jeunemaitre
authors.forename: Ardem
authors.initials: A
authors.lastname: Patapoutian
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000595:Amino Acid Sequence; D000745:Anemia, Hemolytic, Congenital / Q000235:genetics*; D001696:Biomechanical Phenomena; D002648:Child; D004252:DNA Mutational Analysis; D005260:Female; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D015160:Hydrops Fetalis / Q000235:genetics*; D015640:Ion Channel Gating / Q000235:genetics*; D007473:Ion Channels / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D007700:Kinetics; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D011994:Recombinant Proteins / Q000378:metabolism; D055815:Young Adult
chemical_list: D007473:Ion Channels; C515204:PIEZO1 protein, human; D011994:Recombinant Proteins