Multiple clinical forms of dehydrated hereditary stomatocytosis arise from mutations in PIEZO1

被引：260

作者：

Andolfo, Immacolata ^{[1
,2
]}

Alper, Seth L. ^{[3
,4
,5
]}

De Franceschi, Lucia ^{[6
]}

Auriemma, Carla ^{[1
,2
]}

Russo, Roberta ^{[1
,2
]}

De Falco, Luigia ^{[1
,2
]}

Vallefuoco, Fara ^{[1
,2
]}

Esposito, Maria Rosaria ^{[1
,2
]}

Vandorpe, David H. ^{[3
,4
,5
]}

Shmukler, Boris E. ^{[3
,4
,5
]}

Narayan, Rupa ^{[7
]}

Montanaro, Donatella ^{[1
]}

D'Armiento, Maria ^{[8
]}

Vetro, Annalisa ^{[9
]}

Limongelli, Ivan ^{[9
]}

Zuffardi, Orsetta ^{[9
]}

Glader, Bertil E. ^{[7
]}

Schrier, Stanley L. ^{[10
]}

Brugnara, Carlo ^{[11
,12
]}

Stewart, Gordon W. ^{[13
]}

Delaunay, Jean ^{[14
]}

Iolascon, Achille ^{[1
,2
]}

机构：

[1] Univ Naples Federico II, Dept Mol Med & Med Biotechnol, Naples, Italy

[2] Ctr Ingn Genet CEINGE, Naples, Italy

[3] Beth Israel Deaconess Med Ctr, Div Renal, Boston, MA 02215 USA

[4] Beth Israel Deaconess Med Ctr, Vasc Med Div, Boston, MA 02215 USA

[5] Harvard Univ, Sch Med, Dept Med, Boston, MA USA

[6] Univ Verona, Dept Med, I-37100 Verona, Italy

[7] Stanford Univ, Dept Pediat, Sch Med, Div Hematol Oncol, Stanford, CA 94305 USA

[8] Univ Naples Federico II, Dipartimento Sci Biomed Avanzate, Naples, Italy

[9] Univ Pavia, Dept Mol Med, I-27100 Pavia, Italy

[10] Stanford Univ, Dept Med, Sch Med, Div Hematol, Stanford, CA 94305 USA

[11] Harvard Univ, Sch Med, Boston Childrens Hosp, Dept Lab Med, Boston, MA USA

[12] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA

[13] UCL, Div Med, London, England

[14] Univ Paris 11, Fac Med Paris Sud, INSERM, Paris, France

来源：

BLOOD | 2013年 / 121卷 / 19期

关键词：

MECHANICAL CHANNEL; MISSENSE MUTATIONS; HEMOLYTIC ANEMIA; PERINATAL EDEMA; XEROCYTOSIS; MEMBRANE; PSEUDOHYPERKALEMIA; ASCITES; DISEASE; PROTEIN;

D O I：

10.1182/blood-2013-02-482489

中图分类号：

R5 [内科学];

学科分类号：

100201 [内科学];

摘要：

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.

引用

页码：3925 / 3935

页数：11

共 49 条

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