title: Multiple clinical forms of dehydrated hereditary stomatocytosis arise from mutations in PIEZO1.
abstract: Autosomal dominant dehydrated hereditary stomatocytosis (DHSt) usually presents as a compensated hemolytic anemia with macrocytosis and abnormally shaped red blood cells (RBCs). DHSt is part of a pleiotropic syndrome that may also exhibit pseudohyperkalemia and perinatal edema. We identified PIEZO1 as the disease gene for pleiotropic DHSt in a large kindred by exome sequencing analysis within the previously mapped 16q23-q24 interval. In 26 affected individuals among 7 multigenerational DHSt families with the pleiotropic syndrome, 11 heterozygous PIEZO1 missense mutations cosegregated with disease. PIEZO1 is expressed in the plasma membranes of RBCs and its messenger RNA, and protein levels increase during in vitro erythroid differentiation of CD34(+) cells. PIEZO1 is also expressed in liver and bone marrow during human and mouse development. We suggest for the first time a correlation between a PIEZO1 mutation and perinatal edema. DHSt patient red cells with the R2456H mutation exhibit increased ion-channel activity. Functional studies of PIEZO1 mutant R2488Q expressed in Xenopus oocytes demonstrated changes in ion-channel activity consistent with the altered cation content of DHSt patient red cells. Our findings provide direct evidence that R2456H and R2488Q mutations in PIEZO1 alter mechanosensitive channel regulation, leading to increased cation transport in erythroid cells.
authors.affiliation: Department of Molecular Medicine and Medical Biotechnologies, Federico II University of Naples, Naples, Italy.
authors.forename: Immacolata
authors.initials: I
authors.lastname: Andolfo
authors.forename: Seth L
authors.initials: SL
authors.lastname: Alper
authors.forename: Lucia
authors.initials: L
authors.lastname: De Franceschi
authors.forename: Carla
authors.initials: C
authors.lastname: Auriemma
authors.forename: Roberta
authors.initials: R
authors.lastname: Russo
authors.forename: Luigia
authors.initials: L
authors.lastname: De Falco
authors.forename: Fara
authors.initials: F
authors.lastname: Vallefuoco
authors.forename: Maria Rosaria
authors.initials: MR
authors.lastname: Esposito
authors.forename: David H
authors.initials: DH
authors.lastname: Vandorpe
authors.forename: Boris E
authors.initials: BE
authors.lastname: Shmukler
authors.forename: Rupa
authors.initials: R
authors.lastname: Narayan
authors.forename: Donatella
authors.initials: D
authors.lastname: Montanaro
authors.forename: Maria
authors.initials: M
authors.lastname: D'Armiento
authors.forename: Annalisa
authors.initials: A
authors.lastname: Vetro
authors.forename: Ivan
authors.initials: I
authors.lastname: Limongelli
authors.forename: Orsetta
authors.initials: O
authors.lastname: Zuffardi
authors.forename: Bertil E
authors.initials: BE
authors.lastname: Glader
authors.forename: Stanley L
authors.initials: SL
authors.lastname: Schrier
authors.forename: Carlo
authors.initials: C
authors.lastname: Brugnara
authors.forename: Gordon W
authors.initials: GW
authors.lastname: Stewart
authors.forename: Jean
authors.initials: J
authors.lastname: Delaunay
authors.forename: Achille
authors.initials: A
authors.lastname: Iolascon
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D000745:Anemia, Hemolytic, Congenital / Q000145:classification / Q000175:diagnosis / Q000235:genetics*; D000818:Animals; D004622:Embryo, Mammalian; D005260:Female; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D015160:Hydrops Fetalis / Q000145:classification / Q000175:diagnosis / Q000235:genetics*; D007473:Ion Channels / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D008969:Molecular Sequence Data; D009154:Mutation / Q000502:physiology; D010375:Pedigree; D017386:Sequence Homology, Amino Acid; D014162:Transfection; D014982:Xenopus laevis
chemical_list: D007473:Ion Channels; C515204:PIEZO1 protein, human