RBCC Red Blood Cell Collection

PIEZO1 (FAM38A, KIAA0233) [Confidence: high (present in two of the MS resources)]
Piezo-type mechanosensitive ion channel component 1 (Membrane protein induced by beta-amyloid treatment; Mib; Protein FAM38A)

hRBCD IPI00006093
IPI00006093 Protein FAM38A Protein FAM38A membrane n/a 1 4 7 5 n/a 5 2 2 n/a 6 3 2 4 n/a 4 4 n/a 1 2 not mentioned n/a found at its expected molecular weight found at molecular weight

UniProt Q92508
ID PIEZ1_HUMAN Reviewed; 2521 AA.
AC Q92508; A6NHT9; A7E2B7; Q0KKZ9;
DT 18-OCT-2001, integrated into UniProtKB/Swiss-Prot.
read moreDT 11-JAN-2011, sequence version 4.
DT 22-JAN-2014, entry version 110.
DE RecName: Full=Piezo-type mechanosensitive ion channel component 1;
DE AltName: Full=Membrane protein induced by beta-amyloid treatment;
DE Short=Mib;
DE AltName: Full=Protein FAM38A;
GN Name=PIEZO1; Synonyms=FAM38A, KIAA0233;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15616553; DOI=10.1038/nature03187;
RA Martin J., Han C., Gordon L.A., Terry A., Prabhakar S., She X.,
RA Xie G., Hellsten U., Chan Y.M., Altherr M., Couronne O., Aerts A.,
RA Bajorek E., Black S., Blumer H., Branscomb E., Brown N.C., Bruno W.J.,
RA Buckingham J.M., Callen D.F., Campbell C.S., Campbell M.L.,
RA Campbell E.W., Caoile C., Challacombe J.F., Chasteen L.A.,
RA Chertkov O., Chi H.C., Christensen M., Clark L.M., Cohn J.D.,
RA Denys M., Detter J.C., Dickson M., Dimitrijevic-Bussod M., Escobar J.,
RA Fawcett J.J., Flowers D., Fotopulos D., Glavina T., Gomez M.,
RA Gonzales E., Goodstein D., Goodwin L.A., Grady D.L., Grigoriev I.,
RA Groza M., Hammon N., Hawkins T., Haydu L., Hildebrand C.E., Huang W.,
RA Israni S., Jett J., Jewett P.B., Kadner K., Kimball H., Kobayashi A.,
RA Krawczyk M.-C., Leyba T., Longmire J.L., Lopez F., Lou Y., Lowry S.,
RA Ludeman T., Manohar C.F., Mark G.A., McMurray K.L., Meincke L.J.,
RA Morgan J., Moyzis R.K., Mundt M.O., Munk A.C., Nandkeshwar R.D.,
RA Pitluck S., Pollard M., Predki P., Parson-Quintana B., Ramirez L.,
RA Rash S., Retterer J., Ricke D.O., Robinson D.L., Rodriguez A.,
RA Salamov A., Saunders E.H., Scott D., Shough T., Stallings R.L.,
RA Stalvey M., Sutherland R.D., Tapia R., Tesmer J.G., Thayer N.,
RA Thompson L.S., Tice H., Torney D.C., Tran-Gyamfi M., Tsai M.,
RA Ulanovsky L.E., Ustaszewska A., Vo N., White P.S., Williams A.L.,
RA Wills P.L., Wu J.-R., Wu K., Yang J., DeJong P., Bruce D.,
RA Doggett N.A., Deaven L., Schmutz J., Grimwood J., Richardson P.,
RA Rokhsar D.S., Eichler E.E., Gilna P., Lucas S.M., Myers R.M.,
RA Rubin E.M., Pennacchio L.A.;
RT "The sequence and analysis of duplication-rich human chromosome 16.";
RL Nature 432:988-994(2004).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 432-2521, AND TISSUE SPECIFICITY.
RX PubMed=16854388; DOI=10.1016/j.brainres.2006.06.050;
RA Satoh K., Hata M., Takahara S., Tsuzaki H., Yokota H., Akatsu H.,
RA Yamamoto T., Kosaka K., Yamada T.;
RT "A novel membrane protein, encoded by the gene covering KIAA0233, is
RT transcriptionally induced in senile plaque-associated astrocytes.";
RL Brain Res. 1108:19-27(2006).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 486-2521.
RC TISSUE=Bone marrow;
RX PubMed=9039502; DOI=10.1093/dnares/3.5.321;
RA Nagase T., Seki N., Ishikawa K., Ohira M., Kawarabayasi Y., Ohara O.,
RA Tanaka A., Kotani H., Miyajima N., Nomura N.;
RT "Prediction of the coding sequences of unidentified human genes. VI.
RT The coding sequences of 80 new genes (KIAA0201-KIAA0280) deduced by
RT analysis of cDNA clones from cell line KG-1 and brain.";
RL DNA Res. 3:321-329(1996).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 486-2521.
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [5]
RP PROTEIN SEQUENCE OF 955-972; 1324-1334; 1548-1562 AND 1656-1671,
RP VARIANTS DHS ARG-2225 AND HIS-2456, SUBCELLULAR LOCATION, AND TISSUE
RP SPECIFICITY.
RX PubMed=22529292; DOI=10.1182/blood-2012-04-422253;
RA Zarychanski R., Schulz V.P., Houston B.L., Maksimova Y., Houston D.S.,
RA Smith B., Rinehart J., Gallagher P.G.;
RT "Mutations in the mechanotransduction protein PIEZO1 are associated
RT with hereditary xerocytosis.";
RL Blood 120:1908-1915(2012).
RN [6]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=17081983; DOI=10.1016/j.cell.2006.09.026;
RA Olsen J.V., Blagoev B., Gnad F., Macek B., Kumar C., Mortensen P.,
RA Mann M.;
RT "Global, in vivo, and site-specific phosphorylation dynamics in
RT signaling networks.";
RL Cell 127:635-648(2006).
RN [7]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1391; SER-1646 AND
RP THR-1854, AND MASS SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [8]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-2294, AND MASS
RP SPECTROMETRY.
RC TISSUE=Leukemic T-cell;
RX PubMed=19349973; DOI=10.1038/nbt.1532;
RA Wollscheid B., Bausch-Fluck D., Henderson C., O'Brien R., Bibel M.,
RA Schiess R., Aebersold R., Watts J.D.;
RT "Mass-spectrometric identification and relative quantification of N-
RT linked cell surface glycoproteins.";
RL Nat. Biotechnol. 27:378-386(2009).
RN [9]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1646, AND MASS
RP SPECTROMETRY.
RC TISSUE=Leukemic T-cell;
RX PubMed=19690332; DOI=10.1126/scisignal.2000007;
RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K.,
RA Rodionov V., Han D.K.;
RT "Quantitative phosphoproteomic analysis of T cell receptor signaling
RT reveals system-wide modulation of protein-protein interactions.";
RL Sci. Signal. 2:RA46-RA46(2009).
RN [10]
RP FUNCTION, AND SUBCELLULAR LOCATION.
RX PubMed=20016066; DOI=10.1242/jcs.056424;
RA McHugh B.J., Buttery R., Lad Y., Banks S., Haslett C., Sethi T.;
RT "Integrin activation by Fam38A uses a novel mechanism of R-Ras
RT targeting to the endoplasmic reticulum.";
RL J. Cell Sci. 123:51-61(2010).
RN [11]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1391 AND SER-1646, AND
RP MASS SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S.,
RA Mann M.;
RT "Quantitative phosphoproteomics reveals widespread full
RT phosphorylation site occupancy during mitosis.";
RL Sci. Signal. 3:RA3-RA3(2010).
RN [12]
RP VARIANTS DHS SER-718; SER-782; GLN-808; LEU-1117; ASP-2003; VAL-2020;
RP MET-2127; 2166-LYS--LYS-2169 DEL; HIS-2456 AND GLN-2488,
RP CHARACTERIZATION OF VARIANTS DHS HIS-2456 AND GLN-2488, SUBCELLULAR
RP LOCATION, TISSUE SPECIFICITY, AND DEVELOPMENTAL STAGE.
RX PubMed=23479567; DOI=10.1182/blood-2013-02-482489;
RA Andolfo I., Alper S.L., De Franceschi L., Auriemma C., Russo R.,
RA De Falco L., Vallefuoco F., Esposito M.R., Vandorpe D.H.,
RA Shmukler B.E., Narayan R., Montanaro D., D'Armiento M., Vetro A.,
RA Limongelli I., Zuffardi O., Glader B.E., Schrier S.L., Brugnara C.,
RA Stewart G.W., Delaunay J., Iolascon A.;
RT "Multiple clinical forms of dehydrated hereditary stomatocytosis arise
RT from mutations in PIEZO1.";
RL Blood 121:3925-3935(2013).
RN [13]
RP VARIANTS DHS PRO-1358; THR-2020; MET-2127 AND LEU-GLU-2496 INS, AND
RP CHARACTERIZATION OF VARIANTS DHS PRO-1358; THR-2020; MET-2127;
RP LEU-GLU-2496 INS; ARG-2225 AND HIS-2456.
RX PubMed=23695678; DOI=10.1038/ncomms2899;
RA Albuisson J., Murthy S.E., Bandell M., Coste B., Louis-Dit-Picard H.,
RA Mathur J., Feneant-Thibault M., Tertian G., de Jaureguiberry J.P.,
RA Syfuss P.Y., Cahalan S., Garcon L., Toutain F., Simon Rohrlich P.,
RA Delaunay J., Picard V., Jeunemaitre X., Patapoutian A.;
RT "Dehydrated hereditary stomatocytosis linked to gain-of-function
RT mutations in mechanically activated PIEZO1 ion channels.";
RL Nat. Commun. 4:1884-1884(2013).
CC -!- FUNCTION: Pore-forming subunit of a mechanosensitive non-specific
CC cation channel, that conducts both sodium and potassium ions.
CC Plays a key role in epithelial cell adhesion by maintaining
CC integrin activation through R-Ras recruitment to the ER, most
CC probably in its activated state, and subsequent stimulation of
CC calpain signaling.
CC -!- SUBUNIT: Homooligomer, most likely homotetramer (By similarity).
CC -!- SUBCELLULAR LOCATION: Endoplasmic reticulum membrane; Multi-pass
CC membrane protein. Endoplasmic reticulum-Golgi intermediate
CC compartment membrane. Cell membrane; Multi-pass membrane protein.
CC Note=In erythrocytes, located in the plasma membrane.
CC -!- TISSUE SPECIFICITY: Expressed in numerous tissues. In normal
CC brain, expressed exclusively in neurons, not in astrocytes. In
CC Alzheimer disease brains, expressed in about half of the activated
CC astrocytes located around classical senile plaques. In Parkinson
CC disease substantia nigra, not detected in melanin-containing
CC neurons nor in activated astrocytes. Expressed in erythrocytes (at
CC protein level).
CC -!- DEVELOPMENTAL STAGE: At 17 weeks of gestation, strongly expressed
CC in hepatic erythroblasts. At that stage, also expressed in fetal
CC splenic plasma cells and in lymphatic vessel of fetal peritoneum.
CC In vitro, up-regulated during the erythroid differentiation of
CC CD34+ cells from healthy donors (at protein level).
CC -!- DISEASE: Dehydrated hereditary stomatocytosis with or without
CC pseudohyperkalemia and/or perinatal edema (DHS) [MIM:194380]: An
CC autosomal dominant hemolytic anemia characterized by primary
CC erythrocyte dehydration. DHS erythrocytes exhibit decreased total
CC cation and potassium content that are not accompanied by a
CC proportional net gain of sodium and water. DHS patients typically
CC exhibit mild to moderate compensated hemolytic anemia, with an
CC increased erythrocyte mean corpuscular hemoglobin concentration
CC and a decreased osmotic fragility, both of which reflect cellular
CC dehydration. Patients may also show perinatal edema and
CC pseudohyperkalemia due to loss of potassium from red cells stored
CC at room temperature. A minor proportion of red cells appear as
CC stomatocytes on blood films. Complications such as splenomegaly
CC and cholelithiasis, resulting from increased red cell trapping in
CC the spleen and elevated bilirubin levels, respectively, may occur.
CC The course of DHS is frequently associated with iron overload,
CC which may lead to hepatosiderosis. Note=The disease is caused by
CC mutations affecting the gene represented in this entry. All
CC disease-causing mutations characterized so far produce a gain-of-
CC function phenotype, mutated channels exhibiting increased cation
CC transport in erythroid cells, that could be due to slower channel
CC inactivation rate compared to the wild-type protein.
CC -!- MISCELLANEOUS: Piezo comes from the Greek 'piesi' meaning
CC pressure.
CC -!- SIMILARITY: Belongs to the PIEZO family.
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DR EMBL; AC138028; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AB161230; BAF03565.1; -; mRNA.
DR EMBL; D87071; BAA13240.1; -; mRNA.
DR EMBL; BC150271; AAI50272.1; -; mRNA.
DR RefSeq; NP_001136336.2; NM_001142864.2.
DR UniGene; Hs.377001; -.
DR UniGene; Hs.592074; -.
DR ProteinModelPortal; Q92508; -.
DR MINT; MINT-4991257; -.
DR STRING; 9606.ENSP00000301015; -.
DR TCDB; 1.A.75.1.1; the mechanical nociceptor, piezo (piezo) family.
DR PhosphoSite; Q92508; -.
DR DMDM; 209572749; -.
DR PaxDb; Q92508; -.
DR PRIDE; Q92508; -.
DR Ensembl; ENST00000301015; ENSP00000301015; ENSG00000103335.
DR GeneID; 9780; -.
DR KEGG; hsa:9780; -.
DR UCSC; uc010vpb.2; human.
DR CTD; 9780; -.
DR GeneCards; GC16M088781; -.
DR H-InvDB; HIX0022749; -.
DR H-InvDB; HIX0173225; -.
DR HGNC; HGNC:28993; PIEZO1.
DR HPA; HPA047185; -.
DR MIM; 194380; phenotype.
DR MIM; 611184; gene.
DR neXtProt; NX_Q92508; -.
DR Orphanet; 3202; Dehydrated hereditary stomatocytosis.
DR eggNOG; NOG298938; -.
DR HOVERGEN; HBG107901; -.
DR InParanoid; Q92508; -.
DR OMA; SSNCTEP; -.
DR OrthoDB; EOG7J445T; -.
DR GenomeRNAi; 9780; -.
DR NextBio; 36824; -.
DR PRO; PR:Q92508; -.
DR ArrayExpress; Q92508; -.
DR Bgee; Q92508; -.
DR CleanEx; HS_FAM38A; -.
DR Genevestigator; Q92508; -.
DR GO; GO:0005783; C:endoplasmic reticulum; IDA:UniProtKB.
DR GO; GO:0005789; C:endoplasmic reticulum membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0033116; C:endoplasmic reticulum-Golgi intermediate compartment membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0016021; C:integral to membrane; IEA:UniProtKB-KW.
DR GO; GO:0005886; C:plasma membrane; ISS:UniProtKB.
DR GO; GO:0005261; F:cation channel activity; ISS:UniProtKB.
DR GO; GO:0008381; F:mechanically-gated ion channel activity; IEA:Ensembl.
DR GO; GO:0050982; P:detection of mechanical stimulus; IEA:Ensembl.
DR GO; GO:0033634; P:positive regulation of cell-cell adhesion mediated by integrin; IMP:UniProtKB.
DR GO; GO:0033625; P:positive regulation of integrin activation; IMP:UniProtKB.
DR GO; GO:0042391; P:regulation of membrane potential; IEA:Ensembl.
DR InterPro; IPR027272; Piezo.
DR PANTHER; PTHR13167; PTHR13167; 1.
DR Pfam; PF12166; DUF3595; 1.
PE 1: Evidence at protein level;
KW Cell membrane; Coiled coil; Complete proteome;
KW Direct protein sequencing; Disease mutation; Endoplasmic reticulum;
KW Glycoprotein; Hereditary hemolytic anemia; Ion channel; Ion transport;
KW Membrane; Phosphoprotein; Reference proteome; Transmembrane;
KW Transmembrane helix; Transport.
FT CHAIN 1 2521 Piezo-type mechanosensitive ion channel
FT component 1.
FT /FTId=PRO_0000186817.
FT TRANSMEM 5 25 Helical; (Potential).
FT TRANSMEM 27 47 Helical; (Potential).
FT TRANSMEM 64 84 Helical; (Potential).
FT TRANSMEM 118 138 Helical; (Potential).
FT TRANSMEM 194 214 Helical; (Potential).
FT TRANSMEM 218 238 Helical; (Potential).
FT TRANSMEM 248 268 Helical; (Potential).
FT TRANSMEM 302 322 Helical; (Potential).
FT TRANSMEM 428 448 Helical; (Potential).
FT TRANSMEM 460 480 Helical; (Potential).
FT TRANSMEM 514 534 Helical; (Potential).
FT TRANSMEM 579 599 Helical; (Potential).
FT TRANSMEM 602 622 Helical; (Potential).
FT TRANSMEM 629 649 Helical; (Potential).
FT TRANSMEM 681 701 Helical; (Potential).
FT TRANSMEM 823 843 Helical; (Potential).
FT TRANSMEM 852 872 Helical; (Potential).
FT TRANSMEM 926 946 Helical; (Potential).
FT TRANSMEM 987 1007 Helical; (Potential).
FT TRANSMEM 1043 1063 Helical; (Potential).
FT TRANSMEM 1160 1180 Helical; (Potential).
FT TRANSMEM 1184 1204 Helical; (Potential).
FT TRANSMEM 1218 1240 Helical; (Potential).
FT TRANSMEM 1247 1264 Helical; (Potential).
FT TRANSMEM 1277 1297 Helical; (Potential).
FT TRANSMEM 1678 1698 Helical; (Potential).
FT TRANSMEM 1700 1720 Helical; (Potential).
FT TRANSMEM 1734 1754 Helical; (Potential).
FT TRANSMEM 1962 1982 Helical; (Potential).
FT TRANSMEM 2003 2023 Helical; (Potential).
FT TRANSMEM 2032 2052 Helical; (Potential).
FT TRANSMEM 2061 2081 Helical; (Potential).
FT TRANSMEM 2100 2122 Helical; (Potential).
FT TRANSMEM 2129 2149 Helical; (Potential).
FT TRANSMEM 2177 2197 Helical; (Potential).
FT TRANSMEM 2432 2452 Helical; (Potential).
FT COILED 1339 1368 Potential.
FT COMPBIAS 6 91 Leu-rich.
FT MOD_RES 1391 1391 Phosphoserine.
FT MOD_RES 1646 1646 Phosphoserine.
FT MOD_RES 1854 1854 Phosphothreonine.
FT CARBOHYD 295 295 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 2294 2294 N-linked (GlcNAc...).
FT VARIANT 718 718 G -> S (in DHS).
FT /FTId=VAR_069822.
FT VARIANT 782 782 G -> S (in DHS).
FT /FTId=VAR_069823.
FT VARIANT 808 808 R -> Q (in DHS).
FT /FTId=VAR_069824.
FT VARIANT 1117 1117 S -> L (in DHS).
FT /FTId=VAR_069825.
FT VARIANT 1358 1358 R -> P (in DHS; gives rise to
FT mechanically activated currents that
FT inactivate more slowly than wild-type
FT currents).
FT /FTId=VAR_069826.
FT VARIANT 2003 2003 A -> D (in DHS).
FT /FTId=VAR_069827.
FT VARIANT 2020 2020 A -> T (in DHS; gives rise to
FT mechanically activated currents that
FT inactivate more slowly than wild-type
FT currents).
FT /FTId=VAR_069828.
FT VARIANT 2020 2020 A -> V (in DHS).
FT /FTId=VAR_069829.
FT VARIANT 2127 2127 T -> M (in DHS; gives rise to
FT mechanically activated currents that
FT inactivate more slowly than wild-type
FT currents).
FT /FTId=VAR_069830.
FT VARIANT 2166 2169 Missing (in DHS).
FT /FTId=VAR_069831.
FT VARIANT 2225 2225 M -> R (in DHS; gives rise to
FT mechanically activated currents that
FT inactivate more slowly than wild-type
FT currents).
FT /FTId=VAR_069832.
FT VARIANT 2456 2456 R -> H (in DHS; gives rise to
FT mechanically activated currents that
FT inactivate more slowly than wild-type
FT currents).
FT /FTId=VAR_069833.
FT VARIANT 2488 2488 R -> Q (in DHS; increased cation
FT transport in erythroid cells).
FT /FTId=VAR_069834.
FT VARIANT 2496 2496 E -> ELE (in DHS; gives rise to
FT mechanically activated currents that
FT inactivate more slowly than wild-type
FT currents).
FT /FTId=VAR_069835.
FT CONFLICT 750 750 Missing (in Ref. 3; BAA13240 and 4;
FT AAI50272).
SQ SEQUENCE 2521 AA; 286790 MW; 127A3DA3E7CBD2DD CRC64;
MEPHVLGAVL YWLLLPCALL AACLLRFSGL SLVYLLFLLL LPWFPGPTRC GLQGHTGRLL
RALLGLSLLF LVAHLALQIC LHIVPRLDQL LGPSCSRWET LSRHIGVTRL DLKDIPNAIR
LVAPDLGILV VSSVCLGICG RLARNTRQSP HPRELDDDER DVDASPTAGL QEAATLAPTR
RSRLAARFRV TAHWLLVAAG RVLAVTLLAL AGIAHPSALS SVYLLLFLAL CTWWACHFPI
STRGFSRLCV AVGCFGAGHL ICLYCYQMPL AQALLPPAGI WARVLGLKDF VGPTNCSSPH
ALVLNTGLDW PVYASPGVLL LLCYATASLR KLRAYRPSGQ RKEAAKGYEA RELELAELDQ
WPQERESDQH VVPTAPDTEA DNCIVHELTG QSSVLRRPVR PKRAEPREAS PLHSLGHLIM
DQSYVCALIA MMVWSITYHS WLTFVLLLWA CLIWTVRSRH QLAMLCSPCI LLYGMTLCCL
RYVWAMDLRP ELPTTLGPVS LRQLGLEHTR YPCLDLGAML LYTLTFWLLL RQFVKEKLLK
WAESPAALTE VTVADTEPTR TQTLLQSLGE LVKGVYAKYW IYVCAGMFIV VSFAGRLVVY
KIVYMFLFLL CLTLFQVYYS LWRKLLKAFW WLVVAYTMLV LIAVYTFQFQ DFPAYWRNLT
GFTDEQLGDL GLEQFSVSEL FSSILVPGFF LLACILQLHY FHRPFMQLTD MEHVSLPGTR
LPRWAHRQDA VSGTPLLREE QQEHQQQQQE EEEEEEDSRD EGLGVATPHQ ATQVPEGAAK
WGLVAERLLE LAAGFSDVLS RVQVFLRRLL ELHVFKLVAL YTVWVALKEV SVMNLLLVVL
WAFALPYPRF RPMASCLSTV WTCVIIVCKM LYQLKVVNPQ EYSSNCTEPF PNSTNLLPTE
ISQSLLYRGP VDPANWFGVR KGFPNLGYIQ NHLQVLLLLV FEAIVYRRQE HYRRQHQLAP
LPAQAVFASG TRQQLDQDLL GCLKYFINFF FYKFGLEICF LMAVNVIGQR MNFLVTLHGC
WLVAILTRRH RQAIARLWPN YCLFLALFLL YQYLLCLGMP PALCIDYPWR WSRAVPMNSA
LIKWLYLPDF FRAPNSTNLI SDFLLLLCAS QQWQVFSAER TEEWQRMAGV NTDRLEPLRG
EPNPVPNFIH CRSYLDMLKV AVFRYLFWLV LVVVFVTGAT RISIFGLGYL LACFYLLLFG
TALLQRDTRA RLVLWDCLIL YNVTVIISKN MLSLLACVFV EQMQTGFCWV IQLFSLVCTV
KGYYDPKEMM DRDQDCLLPV EEAGIIWDSV CFFFLLLQRR VFLSHYYLHV RADLQATALL
ASRGFALYNA ANLKSIDFHR RIEEKSLAQL KRQMERIRAK QEKHRQGRVD RSRPQDTLGP
KDPGLEPGPD SPGGSSPPRR QWWRPWLDHA TVIHSGDYFL FESDSEEEEE AVPEDPRPSA
QSAFQLAYQA WVTNAQAVLR RRQQEQEQAR QEQAGQLPTG GGPSQEVEPA EGPEEAAAGR
SHVVQRVLST AQFLWMLGQA LVDELTRWLQ EFTRHHGTMS DVLRAERYLL TQELLQGGEV
HRGVLDQLYT SQAEATLPGP TEAPNAPSTV SSGLGAEEPL SSMTDDMGSP LSTGYHTRSG
SEEAVTDPGE REAGASLYQG LMRTASELLL DRRLRIPELE EAELFAEGQG RALRLLRAVY
QCVAAHSELL CYFIIILNHM VTASAGSLVL PVLVFLWAML SIPRPSKRFW MTAIVFTEIA
VVVKYLFQFG FFPWNSHVVL RRYENKPYFP PRILGLEKTD GYIKYDLVQL MALFFHRSQL
LCYGLWDHEE DSPSKEHDKS GEEEQGAEEG PGVPAATTED HIQVEARVGP TDGTPEPQVE
LRPRDTRRIS LRFRRRKKEG PARKGAAAIE AEDREEEEGE EEKEAPTGRE KRPSRSGGRV
RAAGRRLQGF CLSLAQGTYR PLRRFFHDIL HTKYRAATDV YALMFLADVV DFIIIIFGFW
AFGKHSAATD ITSSLSDDQV PEAFLVMLLI QFSTMVVDRA LYLRKTVLGK LAFQVALVLA
IHLWMFFILP AVTERMFNQN VVAQLWYFVK CIYFALSAYQ IRCGYPTRIL GNFLTKKYNH
LNLFLFQGFR LVPFLVELRA VMDWVWTDTT LSLSSWMCVE DIYANIFIIK CSRETEKKYP
QPKGQKKKKI VKYGMGGLII LFLIAIIWFP LLFMSLVRSV VGVVNQPIDV TVTLKLGGYE
PLFTMSAQQP SIIPFTAQAY EELSRQFDPQ PLAMQFISQY SPEDIVTAQI EGSSGALWRI
SPPSRAQMKR ELYNGTADIT LRFTWNFQRD LAKGGTVEYA NEKHMLALAP NSTARRQLAS
LLEGTSDQSV VIPNLFPKYI RAPNGPEANP VKQLQPNEEA DYLGVRIQLR REQGAGATGF
LEWWVIELQE CRTDCNLLPM VIFSDKVSPP SLGFLAGYGI MGLYVSIVLV IGKFVRGFFS
EISHSIMFEE LPCVDRILKL CQDIFLVRET RELELEEELY AKLIFLYRSP ETMIKWTREK
E
//

MIM 194380
*RECORD*
*FIELD* NO
194380
*FIELD* TI
#194380 DEHYDRATED HEREDITARY STOMATOCYTOSIS WITH OR WITHOUT PSEUDOHYPERKALEMIA
AND/OR PERINATAL EDEMA; DHS
read more;;DEHYDRATED HEREDITARY STOMATOCYTOSIS;;
XEROCYTOSIS, HEREDITARY;;
DESICCYTOSIS, HEREDITARY;;
PSEUDOHYPERKALEMIA, FAMILIAL, 1, DUE TO RED CELL LEAK; PSHK1;;
PSEUDOHYPERKALEMIA EDINBURGH
*FIELD* TX
A number sign (#) is used with this entry because of evidence that
dehydrated hereditary stomatocytosis (DHS) is caused by heterozygous
mutation in the PIEZO1 gene (611184) on chromosome 16q24.

DESCRIPTION

Hereditary xerocytosis, also known as dehydrated hereditary
stomatocytosis (DHS), is an autosomal dominant hemolytic anemia
characterized by primary erythrocyte dehydration. DHS erythrocytes
exhibit decreased total cation and potassium content that are not
accompanied by a proportional net gain of sodium and water. DHS patients
typically exhibit mild to moderate compensated hemolytic anemia, with an
increased erythrocyte mean corpuscular hemoglobin concentration and a
decreased osmotic fragility, both of which reflect cellular dehydration
(summary by Zarychanski et al., 2012). Patients may also show perinatal
edema and pseudohyperkalemia due to loss of K+ from red cells stored at
room temperature. A minor proportion of red cells appear as stomatocytes
on blood films. Complications such as splenomegaly and cholelithiasis,
resulting from increased red cell trapping in the spleen and elevated
bilirubin levels, respectively, may occur. The course of DHS is
frequently associated with iron overload, which may lead to
hepatosiderosis (summary by Albuisson et al., 2013).

The 'leaky red blood cells' in familial pseudohyperkalemia show a
temperature-dependent loss of potassium when stored at room temperature,
manifesting as apparent hyperkalemia. The red blood cells show a reduced
life span in vivo, but there is no frank hemolysis. Studies of cation
content and transport show a marginal increase in permeability at 37
degrees C and a degree of cellular dehydration, qualitatively similar to
the changes seen in dehydrated hereditary stomatocytosis. Physiologic
studies show that the passive leak of potassium has an abnormal
temperature dependence, such that the leak is less sensitive to
temperature than that in normal cells (summary by Iolascon et al.,
1999).

- Genetic Heterogeneity of Hereditary Stomatocytosis

Another form of stomatocytosis involving familial pseudohyperkalemia has
been mapped to chromosome 2q35 (609153). There is also an overhydrated
form of hereditary stomatocytosis (OHS; see 185000).

CLINICAL FEATURES

Miller et al. (1971) described a large kindred of Swiss-German origin
with stomatocytosis, in which 3 affected sibs appeared to be homozygous
whereas 50 other affected family members were heterozygous. The
homozygotes had hemolytic anemia, decreased osmotic fragility, increased
intracellular sodium, and marked increase in sodium pump rates. The
heterozygotes had no anemia but had cholelithiasis and intermittent
jaundice. Decreased fragility distinguished it from other forms of
stomatocytosis with hemolytic anemia. Glader et al. (1974) described the
disorder as desiccytosis.

In 16 members of 3 generations of a kindred from Edinburgh, Stewart et
al. (1979) observed elevated plasma potassium if the red cells were not
separated promptly. In vivo plasma potassium concentrations were normal.
Affected persons were not anemic. The authors postulated that digoxin,
which inhibits the red cell sodium-potassium pump, could exacerbate red
cell potassium depletion and lead to frank hemolysis. In the presence of
impaired renal or adrenal function, dangerous hyperkalemia might result.
Luciani et al. (1980) reported an affected mother and daughter. The
family reported by Stewart and Ellory (1985) showed mild hereditary
xerocytosis. James and Stansbie (1987) studied the characteristics of
potassium loss from red cells.

The red blood cells (RBCs) in DHS have a membrane abnormality with
increased permeability to cations with a greater efflux of potassium
than of sodium. Consequently these red cells lose potassium in excess of
sodium gained with a decrease in total cation content. Osmotically
resistant xerocytes result. The disorder was first described as
desiccytosis by Glader et al. (1974). Two patients in a family studied
by Monzon et al. (1981) showed levels of red cell calmodulin 3 to 4
times normal. Exercise-induced hemolysis occurs with marching, jogging,
conga-drumming, karate, and other activities entailing repetitive impact
of the hands or feet on an unyielding surface.

Platt et al. (1981) found that episodes of fatigue, jaundice, pallor,
and darkened urine associated with periods of training in a 21-year-old
world-class competitive freestyle swimmer were the consequence of
xerocytosis. Although most persons, given a hard enough surface and long
enough run, will develop some hemoglobinuria, the most susceptible
persons may have an underlying membrane protein abnormality (Banga et
al., 1979). In their swimmer subject, Platt et al. (1981) demonstrated
that xerocytes are more susceptible than normal red cells to hemolysis
by shear stress. The sensitivity could be partially corrected in vitro
by an experimental maneuver that rehydrates xerocytes. Conversely,
normal erythrocytes could be rendered shear-sensitive by dehydration. At
the other end of the spectrum from xerocytosis is hereditary
stomatocytosis (or hydrocytosis; 185000) in which the red cells are
overhydrated and sodium-loaded.

Vives Corrons et al. (1991) described xerocytosis and chronic hemolytic
anemia related to increased RBC membrane permeability to Na+ and K+. The
red cell trait was thought to have been inherited from the father;
possible deficiency of factor VII (613878) was inherited from the
mother.

Vives Corrons et al. (1995) reported 6 unrelated Spanish families with
11 affected members. They demonstrated unusual heat stability as a
feature of this disorder and suggested that, together with increased
mean corpuscular hemoglobin concentration and decreased RBC osmotic
fragility, the feature is useful for diagnosis of xerocytosis. They
commented that affected persons often show normal or near-normal
hemoglobin levels, despite clinical and laboratory evidence of mild to
moderate hemolysis.

Entezami et al. (1996) described dehydrated hereditary stomatocytosis in
association with perinatal edema. Grootenboer et al. (1998) described a
pleiotropic, autosomal dominant syndrome consisting of DHS, hereditary
pseudohyperkalemia, and severe perinatal edema, including ascites. Edema
spontaneously regressed by 8 months of age. In the family reported by
Grootenboer et al. (1998), the parents of the proband were said to be
unrelated but they were gypsies, raising the possibility of
pseudodominant inheritance of an autosomal recessive disorder. The
proband was found to have ascites 3 weeks before birth on the basis of a
sonogram, and hyperbilirubinemia was found on amniocentesis. Spontaneous
delivery occurred after 31 weeks of pregnancy. At birth there was
generalized edema, with prevailing ascites, hemolytic anemia, and
enlargement of the liver and spleen. Respiratory failure required
mechanical ventilation. During the first 10 days of life, an exchange
transfusion and 2 transfusions of packed red cells were necessary. There
was hyperkalemia in the absence of any abnormality of other plasma
cation concentrations and of the ECG. The ascites acquired a chylous
character during breastfeeding. The mother of the proband had been taken
to hospital at 1 month of age because of ascites and generalized edema
since birth. Ascites receded at 3 months of age. The mother had had a
previous biamniotic twin pregnancy that ended spontaneously at 27 weeks.
One twin had died in utero from generalized edema, including ascites and
pleural and pericardial effusions. The other baby died 24 hours after
birth from an ill-documented reason but reportedly did not display
generalized edema. At the age of 20 years, at the time the proband was
hospitalized, the mother was found to have compensated DHS, as well as
pseudohyperkalemia. The father was hematologically normal. Grootenboer
et al. (1998) suggested that the various manifestations seen in the
mother and at least 2 of her children were the result of mutation at a
single locus.

Carella et al. (1998) referred to this disorder as dehydrated hereditary
stomatocytosis (DHS). It is the most frequent form of the hereditary
stomatocytoses in the set of hemolytic anemias, with an abnormal shape
of the red blood cells resulting from abnormally high membrane
permeability for the monovalent cations Na and K. The clinical
presentation is heterogeneous, ranging from mild to moderate hemolytic
anemia associated with scleral icterus, splenomegaly, and
cholelithiasis. Iron overload may develop later in life. The disorder is
transmitted as an autosomal dominant.

Perel et al. (1999) reported a 15-year-old boy with a dehydrated
hereditary stomatocytosis who underwent splenectomy and developed the
rare postoperative complication of partial portal vein thrombosis. With
prompt heparin therapy, neither propagation of the thrombus nor further
cavernous transformation occurred in the following 6 years. This
complication had previously been reported only in adults with hereditary
stomatocytosis.

Stewart et al. (1996) noted that venous thrombotic complications in
adulthood are a common feature after splenectomy in families with anemia
and hereditary stomatocytosis. Latham et al. (2002) reported a
58-year-old woman, diagnosed with familial pseudohyperkalemia in 1977,
who suffered severe recurrent thromboembolic disease despite an intact
spleen. Her family had previously been reported by Stewart et al. (1979)
and Iolascon et al. (1999). Her red cells showed the classic phenotype
of potassium leakage from cells on standing in vitro, but did not have
stomatocytic morphology.

Iolascon et al. (1999) studied the family in which familial
pseudohyperkalemia was first described by Stewart et al. (1979) and
found that the disorder mapped to the same region of chromosome 16 to
which hereditary xerocytosis had been mapped (see MAPPING). This and the
fact that the red cells in pseudohyperkalemia show a marginal increase
in permeability at 37 degrees C and a degree of cellular dehydration
qualitatively similar to the changes seen in dehydrated hereditary
stomatocytosis suggested that these disorders are allelic.

Rees et al. (2004) noted that 3 families had been reported in which
dehydrated hereditary stomatocytosis was associated with a syndrome of
self-limiting perinatal ascites (Entezami et al., 1996; Grootenboer et
al., 2000; Basu et al., 2003). The authors described a 16-year-old girl
who presented neonatally with abnormal liver function tests and ascites.
A liver biopsy showed hepatitis and fatty changes. The ascites resolved
within 6 months. At the age of 15 years, she developed an episode of
acute hemolysis and was reinvestigated; a diagnosis of dehydrated
hereditary stomatocytosis was made. Pseudohyperkalemia, due to ex vivo
loss of potassium from red cells, was present. The observations
confirmed the previously noted association of dehydrated hereditary
stomatocytosis, pseudohyperkalemia, and perinatal ascites, and suggested
that the ascites is of predominantly hepatic origin.

Carella et al. (2004) noted that 3 clinical forms of pseudohyperkalemia
unassociated with hematologic manifestations, based predominantly on the
leak-temperature dependence curve, had been reported: (1)
pseudohyperkalemia Edinburgh (Stewart et al., 1979), in which the curve
has a shallow slope; (2) pseudohyperkalemia Chiswick or Falkirk
(609153), in which the curve is shouldered; and (3) pseudohyperkalemia
Cardiff (185020), in which the temperature dependence of the leak shows
a 'U-shaped' profile with a minimum at 23 degrees C.

Syfuss et al. (2006) studied a 65-year-old man who had been diagnosed at
55 years of age with hepatosiderosis that was not fully explained by the
heterozygous H63D mutation he carried in the HFE gene (613609.0002); he
did not carry the classic HFE mutation C282Y (613609.0001) and no
mutation was detected in the ferroportin gene (SLC40A1; 604653). Iron
metabolism-related serum parameters were mostly normal, except for an
increased transferrin saturation of 60%, and liver iron concentration
was 62 micromol/g. After observation of an increased percentage of
hyperdense cells and rare stomatocytes or prestomatocytes on blood
smear, ektacytometry was performed, which revealed a leftward shift of
the osmotic gradient curve, indicating an increase in osmotic resistance
and a decrease in cell hydration in a pattern fitting that of DHS.
Review of routine plasma potassium measurements over a 7-year period
showed values fluctuating between high normal and elevated, consistent
with pseudohyperkalemia. Syfuss et al. (2006) noted that although DHS is
known to cause significant iron overload, the unusually mild hematologic
manifestations of DHS in the patient were overlooked. The authors stated
that this patient also had limb-girdle muscular dystrophy (LGMD1A;
159000) that was due to mutation in the myotilin gene (MYOT; 604103) and
believed to be coincidental.

Beaurain et al. (2007) reported a large 3-generation French kindred
exhibiting DHS with pseudohyperkalemia in which 2 branches of the same
family were independently ascertained, with 1 branch having been studied
by Grootenboer et al. (2000) (family 'VA'). Plasma potassium
concentration exceeded 5.0 mmol/L in 8 affected individuals, and was
just below this threshold in another 3 patients. Stomatocytes were
unusually scarce on blood smears from affected members, and in 1 patient
with mild disease, stomatocytes were incompletely formed.

Martinaud et al. (2008) described a woman and her son who both had DHS.
The 60-year-old mother had undergone splenectomy at 27 years of age,
after diagnosis of chronic hemolytic anemia, and over the following
years she suffered at least 5 deep venous thromboses and developed
chronic portal vein thrombosis that resulted in esophageal varices
requiring annual sclerotherapy and ultimately resection. Blood smears
showed 5% stomatocytes, and she displayed a left shift of the osmotic
gradient curve on ecktacytometry, highly characteristic for DHS. Her
28-year-old son, who was asymptomatic except for jaundice, exhibited
blood smears and ektacytometry similar to those of his mother. There was
no evidence of pseudohyperkalemia in either patient. Martinaud et al.
(2008) noted that antiphospholipid antibodies to IgG were present in
both patients, although their association with the disease, if any, was
unclear.

Houston et al. (2011) studied 29 affected and 77 unaffected members of a
large Canadian kindred segregating an autosomal dominant hemolytic
disorder associated with an elevated mean corpuscular hemoglobin
concentration (MCHC) and decreased osmotic fragility, a phenotype most
consistent with hereditary xerocytosis. A history of transient anemia,
jaundice, red or brown urine, red cell transfusion, and either
gallstones or cholecystectomy were all significantly more prevalent in
affected than in unaffected individuals (p less than 0.01). Despite a
mean percent reticulocyte count of 9.7%, affected individuals were not
anemic and their hemoglobin concentrations were not statistically
different from unaffected individuals. Consistent with hemolysis,
affected family members had significantly elevated indirect bilirubin
levels and decreased haptoglobin levels; in addition, serum ferritin was
elevated in all age groups compared to unaffected individuals, and was
greater than 900 micrograms per liter in 7 patients. Osmotic fragility
testing in 10 affected individuals showed that affected red blood cells
were resistant to lysis in progressively hypotonic saline solutions. Red
cell morphology assessments revealed that target cells, schistocytes,
and eccentrocytes were increased in affected individuals, with
eccentrocytes being the most prominent abnormal red cell phenotype.

Andolfo et al. (2013) described a 38-year-old female triathlete who was
first diagnosed with hemolytic anemia at 14 years of age, after a
1-month duration of weakness. A similar episode of weakness recurred in
her 20s, and again at age 32; both episodes resolved spontaneously. The
patient reported chronic yellowing of her eyes without changes in color
of urine or stool and without fever or gastrointestinal symptoms. The
patient's brother was also diagnosed with hemolytic anemia, accompanied
by 50% deficiency of pyruvate kinase (see 266200), and her father was
reported to have mild anemia of unclear etiology. On physical
examination, the patient had mild scleral icterus and hepatomegaly;
peripheral blood smear showed spherocytes, macrocytes, rare
stomatocytes, and tear drop-shaped red cells. Osmotic fragility testing
demonstrated osmotic resistance, and ektacytometry revealed decreased
RBC deformability in hypertonic solutions, supporting the clinical
diagnosis of dehydrated stomatocytosis.

DIAGNOSIS

Albuisson et al. (2013) noted that DHS is a difficult diagnosis to make
because of highly variable clinical expression, ranging from the absence
of clinical features to lethal perinatal edema. Although features of DHS
can include severe iron overload leading to hepatic transplantation or
life-threatening thromboembolic disease after splenectomy, the most
frequent DHS condition is moderately symptomatic hemolysis. In addition,
the only laboratory test for DHS is ektacytometry, which is available in
a limited number of laboratories. The disease may be overlooked for
years or decades, and it is sometimes confused with spherocytosis (see
182900).

INHERITANCE

One instance of male-to-male transmission occurred in the family with
DHS reported by Stewart et al. (1979), consistent with autosomal
dominant inheritance.

The transmission pattern of DHS in a large Irish family reported by
Carella et al. (1998) was consistent with autosomal dominant
inheritance.

MAPPING

Carella et al. (1998) studied a large 3-generation Irish family in which
14 members had dehydrated hereditary stomatocytosis. Two additional
small families were also included in the study. Linkage of DHS was found
to microsatellite markers on the long arm of chromosome 16 (16q23-q24).
A maximum 2-point lod score of 6.62 at recombination fraction 0.00 was
obtained at marker D16S520.

Iolascon et al. (1999) studied the original Edinburgh family in which
familial pseudohyperkalemia was first described by Stewart et al. (1979)
and found that the disorder mapped to the same locus (16q23-qter) that
Carella et al. (1998) had identified for dehydrated hereditary
stomatocytosis.

Grootenboer et al. (2000) studied 10 kindreds, including 8 French and 2
American. Four families had dehydrated hereditary stomatocytosis alone;
3 had DHS and pseudohyperkalemia; 2 had DHS and perinatal edema; and 1
family, which was originally reported by Grootenboer et al. (1998),
exhibited all 3 manifestations. Grootenboer et al. (2000) presented
evidence that DHS with pseudohyperkalemia and perinatal edema is a
pleiotropic syndrome in which some features may be missing.
Specifically, they found linkage to 16q23-q24 in all kindreds with no
evidence of heterogeneity.

In a large 3-generation French family with DHS and pseudohyperkalemia, 1
branch of which had been studied by Grootenboer et al. (2000) (family
'VA'), Beaurain et al. (2007) analyzed 19 microsatellite markers at
chromosome 16q24.1-qter, obtaining 2-point lod scores greater than 3.5
for 8 of the 12 telomeric markers. Multipoint linkage analysis yielded a
maximum lod score of 4.7 for the marker at the start of the telomeric
region, D16S539. Recombination events reduced the disease haplotype to
an 11.45-cM (5.17-Mb) interval from D16S3037 to the 16q telomere.

In a large Canadian kindred segregating autosomal dominant xerocytosis,
Houston et al. (2011) performed linkage analysis using 6 microsatellite
markers within the 16q22.2-q24.3 interval and obtained lod scores
greater than 3.0 at D16S3074, D16S2621, and D16S3026. Recombination
events placed the centromeric boundary between D16S2621 and D16S3026,
thus narrowing the disease interval to 16q24.2-qter and strongly
suggesting that the causative gene was not located between 16q23-q24 as
previously reported.

MOLECULAR GENETICS

Using high-resolution SNP typing in a presumed homozygote from a family
of Swiss-German origin segregating autosomal dominant stomatocytosis,
originally reported by Miller et al. (1971), Zarychanski et al. (2012)
identified a large region of homozygosity within the 16q24.2-qter
interval. Whole-exome sequencing in the Swiss-German family and in a
Canadian DHS kindred previously studied by Houston et al. (2011)
revealed 2 heterozygous missense mutations in the PIEZO1 gene (M2225R,
611184.0001 and R2456H, 611184.0002) that segregated with disease in
each family, respectively.

In a large 4-generation French pedigree with DHS mapping to
16q24.1-qter, previously studied by Grootenboer et al. (2000) (family
'VA') and Beaurain et al. (2007), Albuisson et al. (2013) performed
whole-exome sequencing and identified a heterozygous missense mutation
in the PIEZO1 gene (A2020T; 611184.0003) that segregated with disease.
Screening of the entire coding sequence of PIEZO1 in 2 more DHS
kindreds, previously reported by Grootenboer et al. (2000) (family 'VE')
and Martinaud et al. (2008), respectively, and in 11 unrelated DHS
cases, 1 of which was previously reported by Syfuss et al. (2006),
revealed 3 additional heterozygous mutations in 10 probands, including 2
missense mutations (R1358P, 611184.0004; T2127M, 611184.0005) and a
recurrent 6-bp duplication (611184.0006) that was present in 8 unrelated
index cases. Functional analysis demonstrated that all 6 PIEZO1
mutations identified in DHS patients to date could be defined as
gain-of-function mutations, leading to increased channel activity in
response to a given stimulus.

In an Edinburgh family with DHS and pseudohyperkalemia, originally
reported by Stewart et al. (1979), Andolfo et al. (2013) performed
whole-exome sequencing and identified a missense mutation in the PIEZO1
gene (T2127M; 611184.0005) that segregated with disease and was not
found in 38 unrelated control exomes. Sequencing of PIEZO1 in an
additional 6 families, including 3 French families previously studied by
Grootenboer et al. (2000) (families 'AR,' 'DA,' and 'TR'), a French
Gypsy family originally reported by Grootenboer et al. (1998) and
studied by Grootenboer et al. (2000) as family 'BI,' and an Irish mother
and son previously reported by Carella et al. (1998), revealed
heterozygous mutations in all of them (see, e.g., 611184.0002,
611184.0007, and 611184.0008). In 3 of those families, multiple in cis
missense mutations in PIEZO1 were found (see, e.g., 611184.0007 and
611184.0008); Andolfo et al. (2013) noted that because the linked
variants at sites of lesser evolutionary conservation were not present
among normal alleles or SNP databases, the contribution of each
individual mutation to its linked phenotype could not yet be assigned.

- Exclusion Studies

In a large 4-generation French family with DHS and pseudohyperkalemia
mapping to 16q24.1-qter, Beaurain et al. (2007) sequenced the positional
candidate TUBB3 gene but found no mutations. Southern blot showed no
evidence of deletion or gene rearrangement.

*FIELD* SA
Harm et al. (1979); Nolan (1984); Snyder et al. (1978); Wiley (1984)
*FIELD* RF
1. Albuisson, J.; Murthy, S. E.; Bandell, M.; Coste, B.; Louis-dit-Picard,
H.; Mathur, J.; Feneant-Thibault, M.; Tertian, G.; de Jaureguiberry,
J.-P.; Syfuss, P.-Y.; Cahalan, S.; Garcon, L.; and 6 others: Dehydrated
hereditary stomatocytosis linked to gain-of-function mutations in
mechanically activated PIEZO1 ion channels. Nature Commun. 4: 1884,
2013. Note: Electronic Article.

2. Andolfo, I.; Alper, S. L.; De Franceschi, L.; Auriemma, C.; Russo,
R.; De Falco, L.; Vallefuoco, F.; Esposito, M. R.; Vandorpe, D. H.;
Shmukler, B. E.; Narayan, R.; Montanaro, D.; and 10 others: Multiple
clinical forms of dehydrated hereditary stomatocytosis arise from
mutations in PIEZO1. Blood 121: 3925-3935, 2013.

3. Banga, J. P.; Pinder, J. C.; Gratzer, W. B.; Linch, D. C.; Huehns,
E. R.: An erythrocyte membrane protein anomaly in march haemoglobinuria. Lancet 314:
1048-1049, 1979. Note: Originally Volume II.

4. Basu, A. P.; Carey, P.; Cynober, T.; Chetty, M.; Delaunay, G. W.;
Stewart, G. W.; Richmond, S.: Dehydrated hereditary stomatocytosis
with transient perinatal ascites. Arch. Dis. Child. Fetal Neonatal
Ed. 88: F438-F439, 2003.

5. Beaurain, G.; Mathieu, F.; Grootenboer, S.; Fiquet, B.; Cynober,
T.; Tchernia, G.; Delaunay, J.; Jeunemaitre, X.: Dehydrated hereditary
stomatocytosis mimicking familial hyperkalaemic hypertension: clinical
and genetic investigation. Europ. J. Haemat. 78: 253-259, 2007.

6. Carella, M.; d'Adamo, A. P.; Grootenboer-Mignot, S.; Vantyghem,
M. C.; Esposito, L.; D'Eustacchio, A.; Ficarella, R.; Stewart, G.
W.; Gasparini, P.; Delaunay, J.; Iolascon, A.: A second locus mapping
to 2q35-36 for familial pseudohyperkalaemia. Europ. J. Hum. Genet. 12:
1073-1076, 2004.

7. Carella, M.; Stewart, G.; Ajetunmobi, J. F.; Perrotta, S.; Grootenboer,
S.; Tchernia, G.; Delaunay, J.; Totaro, A.; Zelante, L.; Gasparini,
P.; Iolascon, A.: Genomewide search for dehydrated hereditary stomatocytosis
(hereditary xerocytosis): mapping of locus to chromosome 16 (16q23-qter). Am.
J. Hum. Genet. 63: 810-816, 1998.

8. Entezami, M.; Becker, R.; Menssen, H. D.; Marcinkowski, M.; Versmold,
H. T.: Xerocytosis with concomitant intrauterine ascites: first description
and therapeutic approach. (Letter) Blood 87: 5392-5393, 1996.

9. Glader, B. E.; Fortier, N.; Albala, M. M.; Nathan, D. G.: Congenital
hemolytic anemia associated with dehydrated erythrocytes and increased
potassium loss. New Eng. J. Med. 291: 491-496, 1974.

10. Grootenboer, S.; Schischmanoff, P.-O.; Laurendeau, I.; Cynober,
T.; Tchernia, G.; Dommergues, J.-P.; Dhermy, D.; Bost, M.; Varet,
B.; Snyder, M.; Ballas, S. K.; Ducot, B.; Babron, M.-C.; Stewart,
G. W.; Gasparini, P.; Iolascon, A.; Delaunay, J.: Pleiotropic syndrome
of dehydrated hereditary stomatocytosis, pseudohyperkalemia, and perinatal
edema maps to 16q23-q24. Blood 96: 2599-2605, 2000.

11. Grootenboer, S.; Schischmanoff, P. O.; Cynober, T.; Rodrigue,
J.-C.; Delaunay, J.; Tchernia, G.; Dommergues, J.-P.: A genetic syndrome
associating dehydrated hereditary stomatocytosis, pseudohyperkalaemia
and perinatal oedema. Brit. J. Haemat. 103: 383-386, 1998.

12. Harm, W.; Fortier, N. L.; Lutz, H. U.; Fairbanks, G.; Snyder,
L. M.: Increased erythrocyte lipid peroxidation in hereditary xerocytosis. Clin.
Chim. Acta 99: 121-128, 1979.

13. Houston, B. L.; Zelinski, T.; Israels, S. J.; Coghlan, G.; Chodirker,
B. N.; Gallagher, P. G.; Houston, D. S.; Zarychanski, R.: Refinement
of the hereditary xerocytosis locus on chromosome 16q in a large Canadian
kindred. Blood Cells Molec. Dis. 47: 226-231, 2011.

14. Iolascon, A.; Stewart, G. W.; Ajetunmobi, J. F.; Perrotta, S.;
Delaunay, J.; Carella, M.; Zelante, L.; Gasparini, P.: Familial pseudohyperkalemia
maps to the same locus as dehydrated hereditary stomatocytosis (hereditary
xerocytosis). Blood 93: 3120-3123, 1999.

15. James, D. R.; Stansbie, D.: Familial pseudohyperkalaemia: inhibition
of erythrocyte K+ efflux at 4 degrees C by quinine. Clin. Sci. 73:
557-560, 1987.

16. Latham, T.; Stewart, G. W.; Horn, E. H.: Recurrent thromboembolism
in a familial pseudohyperkalaemia patient with an intact spleen. (Letter) Brit.
J. Haemat. 119: 1137 only, 2002.

17. Luciani, S.-C.; Lavabre-Bertrand, T.; Fourcade, J.; Barjon, P.;
Mimran, A.; Callis, A.: Familial pseudohyperkalaemia. (Letter) Lancet 315:
491 only, 1980. Note: Originally Volume I.

18. Martinaud, C.; Gisserot, O.; Graffin, B.; Gaillard, T.; Brisou,
P.; Cynober, T.; de Jaureguiberry, J.-P.; Delaunay, J.; Aguilon, P.
: Antiphospholipid antibodies in a family with dehydrated hereditary
stomatocytosis. (Letter) Thromb. Res. 122: 572-575, 2008.

19. Miller, D. R.; Rickles, F. R.; Lichtman, M. A.; LaCelle, P. L.;
Bates, J.; Weed, R. I.: A new variant of hereditary hemolytic anemia
with stomatocytosis and erythrocyte cation abnormality. Blood 38:
184-203, 1971.

20. Monzon, C. M.; Burgert, E. O., Jr.; Fairbanks, V. F.; Penniston,
J. J.; Jones, J.: Increased erythrocytic calmodulin in hereditary
xerocytosis. (Abstract) Pediat. Res. 15: 582 only, 1981.

21. Nolan, G. R.: Hereditary xerocytosis: a case history and review
of the literature. Pathology 16: 151-154, 1984.

22. Perel, Y.; Dhermy, D.; Carrere, A.; Chateil, J. F.; Bondonny,
J. M.; Micheau, M.; Barbier, R.: Portal vein thrombosis after splenectomy
for hereditary stomatocytosis in childhood. Europ. J. Pediat. 158:
628-630, 1999.

23. Platt, O. S.; Lux, S. E.; Nathan, D. G.: Exercise-induced hemolysis
in xerocytosis: erythrocyte dehydration and shear sensitivity. J.
Clin. Invest. 68: 631-638, 1981.

24. Rees, D. C.; Portmann, B.; Ball, C.; Mieli-Vergani, G.; Nicolaou,
A.; Chetty, M. C.; Stewart, G. W.: Dehydrated hereditary stomatocytosis
is associated with neonatal hepatitis. Brit. J. Haemat. 126: 272-276,
2004.

25. Snyder, L. M.; Lutz, H. U.; Sauberman, N.; Jacobs, J.; Fortier,
N. L.: Fragmentation and myelin formation in hereditary xerocytosis
and other hemolytic anemias. Blood 52: 750-761, 1978.

26. Stewart, G. W.; Amess, J. A. L.; Eber, S. W.; Kingswood, C.; Lane,
P. A.; Smith, B. D.; Mentzer, W. C.: Thrombo-embolic disease after
splenectomy for hereditary stomatocytosis. Brit. J. Haemat. 93:
303-310, 1996.

27. Stewart, G. W.; Corrall, R. J. M.; Fyffe, J. A.; Stockdill, G.;
Strong, J. A.: Familial pseudohyperkalaemia: a new syndrome. Lancet 314:
175-177, 1979. Note: Originally Volume II.

28. Stewart, G. W.; Ellory, J. C.: A family with mild hereditary
xerocytosis showing high membrane cation permeability at low temperatures. Clin.
Sci. 69: 309-319, 1985.

29. Syfuss, P.-Y.; Ciupea, A.; Brahimi, S.; Cynober, T.; Stewart,
G. W.; Grandchamp, B.; Beaumont, C.; Tchernia, G.; Delaunay, J.; Wagner,
J.-C.: Mild dehydrated hereditary stomatocytosis revealed by marked
hepatosiderosis. Clin. Lab. Haemat. 28: 270-274, 2006.

30. Vives Corrons, J. L.; Besson, I.; Aymerich, M.; Ayala, S.; Alloisio,
N.; Delaunay, J.; Gonzalez, I.; Manrubia, E.: Hereditary xerocytosis:
a report of six unrelated Spanish families with leaky red cell syndrome
and increased heat stability of the erythrocyte membrane. Brit. J.
Haemat. 90: 817-822, 1995.

31. Vives Corrons, J. L.; Besson, I.; Merino, A.; Monteagudo, J.;
Reverter, J. C.; Aguilar, J. L.; Enrich, C.: Occurrence of hereditary
leaky red cell syndrome and partial coagulation factor VII deficiency
in a Spanish family. Acta Haemat. 86: 194-199, 1991.

32. Wiley, J. S.: Inherited red cell dehydration: a hemolytic syndrome
in search of a name. (Editorial) Pathology 16: 115-116, 1984.

33. Zarychanski, R.; Schulz, V. P.; Houston, B. L.; Maksimova, Y.;
Houston, D. S.; Smith, B.; Rinehart, J.; Gallagher, P. G.: Mutations
in the mechanotransduction protein PIEZO1 are associated with hereditary
xerocytosis. Blood 120: 1908-1915, 2012.

*FIELD* CS
INHERITANCE:
Autosomal dominant

HEAD AND NECK:
[Eyes];
Scleral icterus (in some patients)

CARDIOVASCULAR:
[Heart];
Pericardial effusion, perinatal (rare);
[Vascular];
Thrombosis, susceptibility to (post-splenectomy patients)

RESPIRATORY:
[Lung];
Pleural effusion, perinatal (rare)

ABDOMEN:
Ascites, perinatal (in some patients);
[Liver];
Hepatomegaly (in some patients);
Hepatosiderosis (rare);
Hepatitis (rare);
[Biliary tract];
Cholelithiasis (in some patients);
[Spleen];
Splenomegaly (in some patients)

GENITOURINARY:
[Kidneys];
Hemoglobinuria (in some patients)

SKIN, NAILS, HAIR:
[Skin];
Jaundice, intermittent (in some patients);
Pallor (in some patients);
Edema, generalized perinatal (in some patients)

HEMATOLOGY:
Anemia, chronic hemolytic;
Increased reticulocyte count;
Macrocytosis (in some patients);
Increased mean corpuscular hemoglobin concentration;
Stomatocytes (may be few in number);
Eccentrocytes (in some patients);
Ektacytometric osmotic gradient curve shifted to the left;
Increased red blood cell membrane permeability to univalent cations;
Increased red cell hemolysis by shear stress

LABORATORY ABNORMALITIES:
Pseudohyperkalemia, due to ex vivo efflux of potassium from red cells
(in some patients);
Increased serum bilirubin (in some patients);
Decreased serum haptoglobin (in some patients);
Increased serum ferritin (in some patients);
Iron overload (in some patients)

MISCELLANEOUS:
Splenectomy increases thrombotic risk in these patients;
Episodes of fatigue or weakness (in some patients);
Hemolysis may be exercise-induced

MOLECULAR BASIS:
Caused by mutation in the PIEZO1 ion channel gene (PIEZO1, 611184.0001)

*FIELD* CD
John F. Jackson: 6/15/1995

*FIELD* ED
joanna: 07/18/2013

*FIELD* CN
Marla J. F. O'Neill - updated: 7/2/2013
Victor A. McKusick - updated: 10/4/2004
Victor A. McKusick - updated: 1/9/2001
Armand Bottani - updated: 3/14/2000
Victor A. McKusick - updated: 7/13/1999
Victor A. McKusick - updated: 9/16/1998

*FIELD* CD
Victor A. McKusick: 6/2/1986

*FIELD* ED
carol: 10/15/2013
joanna: 7/15/2013
carol: 7/3/2013
carol: 7/2/2013
carol: 4/11/2011
terry: 2/10/2009
terry: 6/24/2005
tkritzer: 10/6/2004
terry: 10/4/2004
joanna: 3/19/2004
carol: 1/24/2001
terry: 1/9/2001
carol: 3/14/2000
terry: 3/14/2000
carol: 7/27/1999
kayiaros: 7/27/1999
jlewis: 7/21/1999
carol: 7/19/1999
terry: 7/13/1999
terry: 5/20/1999
alopez: 9/18/1998
terry: 9/16/1998
terry: 11/2/1995
mimadm: 6/7/1995
carol: 6/15/1992
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/27/1989

MIM 611184
*RECORD*
*FIELD* NO
611184
*FIELD* TI
*611184 PIEZO-TYPE MECHANOSENSITIVE ION CHANNEL COMPONENT 1; PIEZO1
;;FAMILY WITH SEQUENCE SIMILARITY 38, MEMBER A; FAM38A;;
read moreMEMBRANE PROTEIN INDUCED BY BETA-AMYLOID TREATMENT; MIB
*FIELD* TX

DESCRIPTION

Piezos are large transmembrane proteins conserved among various species,
all having between 24 and 36 predicted transmembrane domains. 'Piezo'
comes from the Greek 'piesi,' meaning 'pressure.' The PIEZO1 gene
encodes a protein that induces mechanically activated (MA) currents in
various cell types (Coste et al., 2010).

CLONING

By database analysis of subtracted rat beta-amyloid (see APP;
104760)-induced astrocyte mRNA, followed by screening an amyloid
beta-treated rat astrocyte cDNA library, Satoh et al. (2006) cloned
Fam38a, which they called Mib. They isolated the corresponding human
cDNA using RACE and RT-PCR with oligonucleotide primers based on the
sequence of KIAA0233 (Nagase et al., 1996). The deduced 2,090-amino acid
human FAM38A protein contains a signal sequence, 24 transmembrane
domains, and shares 83.1% amino acid identity with rat Fam38a. Northern
blot analysis detected moderate expression of rat Fam38a in lung and
kidney, and weak expression in heart, spleen, and liver. Double
immunofluorescence studies colocalized rat Fam38a with Serca2 (ATP2A2;
108740) and beta-COP (COPB; 600959), markers for the endoplasmic
reticulum (ER) and ER-Golgi intermediate compartment, respectively. In
situ hybridization analysis of human brain sections detected FAM38A
expression in neurons but not in quiescent astrocytes. In contrast,
brain sections from Alzheimer disease (AD; 104300) patients displayed
FAM38A expression in approximately half of the activated astrocytes
located around classic senile plaques. Satoh et al. (2006) suggested
that induction of FAM38A mRNA in astrocytes may be related to amyloid
beta production.

Using quantitative PCR in adult mouse tissues, Coste et al. (2010)
determined that Piezo1 mRNA expression is highest in lung, skin, and
bladder. Expression was seen in all tissues tested. Coste et al. (2010)
determined that Piezo1 protein is localized at or near the plasma
membrane.

Using mass spectrometry-based proteomic analysis of human erythrocyte
ghosts, Zarychanski et al. (2012) confirmed the presence of the long
isoform of PIEZO1 in human erythrocyte membranes.

Andolfo et al. (2013) analzyed Piezo1 expression during mouse embryonic
development and observed that Piezo1 mRNA increased gradually from
embryonic day 9.5 to 15.5 and was sustained through birth. In addition,
they demonstrated PIEZO1 polypeptide expression in adult RBC membranes
from humans and mice. Immunohistochemical analyses of human 17-week
fetal tissues showed strong cytoplasmic and membrane signals in hepatic
erythroblasts and positive cytoplasmic staining patterns in splenic
plasma cells. Andolfo et al. (2013) observed a marked signal in
lymphatic vessels of the 17-week fetal peritoneum, whereas PIEZO1
immunoreactivity was absent from peritoneal lymphatic vessels of healthy
human adults; the authors stated that this observation provided a first
link between PIEZO1 mutations and perinatal edema (see MOLECULAR
GENETICS).

MAPPING

Using panels of radiation hybrid and human/rodent hybrid cell lines,
Nagase et al. (1996) mapped the FAM38A gene (KIAA0233) to chromosome 16.

GENE FUNCTION

Coste et al. (2010) characterized a rapidly adapting mechanically
activated (MA) current in a mouse neuroblastoma cell line. Expression
profiling and RNA interference knockdown of candidate genes identified
Piezo1 (FAM38A) as required for MA currents in these cells. Piezo1 and
the related Piezo2 (FAM38B; 613629) are vertebrate multipass
transmembrane proteins with homologs in invertebrates, plants, and
protozoa. Overexpression of mouse Piezo1 and Piezo2 induced 2
kinetically distinct MA currents. Piezos are expressed in several
tissues, and knockdown of Piezo2 in dorsal root ganglia neurons
specifically reduced rapidly adapting MA currents. Coste et al. (2010)
proposed that Piezos are components of MA cation channels.

Coste et al. (2012) showed that mouse Piezo1 and Piezo2 induce
mechanically activated cationic currents in cells. They showed that
Drosophila melanogaster Piezo also induces mechanically activated
currents in cells, but through channels with remarkably distinct pore
properties including sensitivity to the pore blocker ruthenium red and
single channel conductances. Mouse Piezo1 assembles as an approximately
1.2 million-dalton homooligomer, with no evidence of other proteins in
this complex. Purified mouse Piezo1 reconstituted into asymmetric lipid
bilayers and liposomes forms ruthenium red-sensitive ion channels. Coste
et al. (2012) concluded that their data demonstrated that Piezo proteins
are an evolutionarily conserved ion channel family involved in
mechanotransduction.

Kim et al. (2012) studied the physiologic role of Drosophila Piezo and
showed that Drosophila Piezo expression in human cells induces
mechanically activated currents, similar to its mammalian counterparts.
Behavioral responses to noxious mechanical stimuli were severely reduced
in Drosophila Piezo knockout larvae, whereas responses to another
noxious stimulus (high temperature) or touch were not affected. Knocking
down Drosophila Piezo in sensory neurons that mediate nociception and
express the DEG/ENaC ion channel pickpocket (ppk) was sufficient to
impair responses to noxious mechanical stimuli. Furthermore, expression
of Drosophila Piezo in these same neurons rescued the phenotype of the
constitutive Drosophila Piezo knockout larvae. Accordingly,
electrophysiologic recordings from ppk-positive neurons revealed a
Drosophila Piezo-dependent, mechanically activated current. Finally, Kim
et al. (2012) found that Drosophila Piezo and ppk function in parallel
pathways in ppk-positive cells, and that mechanical nociception is
abolished in the absence of both channels. Kim et al. (2012) concluded
that their data demonstrated the physiologic relevance of the Piezo
family in mechanotransduction in vivo, supporting a role of Piezo
proteins in mechanosensory nociception.

Andolfo et al. (2013) induced erythroid differentiation of CD34+ cells
from healthy controls and found that PIEZO1 mRNA was significantly
upregulated after 14 days of erythropoietin treatment. In the same cell
systems, PIEZO1 colocalized with the plasma membrane marker glycophorin
(see 111300) at days 7 and 14. No PIEZO1 immunoreactivity was detected
in day 0 CD34+ cells.

MOLECULAR GENETICS

In 2 unrelated families with dehydrated hereditary stomatocytosis (DHS;
194380), Zarychanski et al. (2012) identified heterozygosity for 2
missense mutations in the PIEZO1 gene (M2225R, 611184.0001 and R2456H,
611184.0002) that segregated with disease in each family, respectively.

In 3 DHS kindreds and 8 unrelated DHS cases, Albuisson et al. (2013)
identified heterozygosity for 3 missense mutations
(622284.0003-611184.0005) and a recurrent 6-bp duplication
(611184.0006). The mutations segregated fully with disease in the
families. Functional analysis demonstrated that all 6 PIEZO1 mutations
identified in DHS patients to date could be defined as gain-of-function
mutations, leading to increased channel activity in response to a given
stimulus.

In 7 families with DHS, Andolfo et al. (2013) sequenced the PIEZO1 gene
and identified heterozygosity for missense mutations (see, e.g.,
611184.0002, 611184.0005, 611184.0007, and 611184.0008). In 3 of the
families, multiple in cis missense mutations in PIEZO1 were found (see,
e.g., 611184.0007 and 611184.0008); Andolfo et al. (2013) stated that
because the linked variants at sites of lesser evolutionary conservation
were not present among normal alleles or SNP databases, the contribution
of each individual mutation to its linked phenotype could not yet be
assigned.

*FIELD* AV
.0001
DEHYDRATED HEREDITARY STOMATOCYTOSIS
PIEZO1, MET2225ARG

In affected members of a large family of Swiss-German origin with
dehydrated hereditary stomatocytosis (DHS; 194380), originally reported
by Miller et al. (1971), Zarychanski et al. (2012) identified
heterozygosity for a T-to-G transversion at nucleotide position
Chr16:88,783,293 (GRCh37) in exon 46 of the PIEZO1 gene, resulting in a
met2225-to-arg (M2225R) substitution at a highly conserved residue in
the C-terminal region. The mutation was not found in unaffected family
members, in dbSNP v135, or in approximately 3,200 alleles of the NHLBI
Exome Sequencing Project.

.0002
DEHYDRATED HEREDITARY STOMATOCYTOSIS
PIEZO1, ARG2456HIS

In affected members from a large Canadian family with dehydrated
hereditary stomatocytosis (DHS; 194380), originally reported by Houston
et al. (2011), Zarychanski et al. (2012) identified heterozygosity for a
G-to-A transition at position Chr16:88,782,212 (GRCh37) in exon 51 of
the PIEZO1 gene, resulting in an arg2456-to-his (R2456H) substitution at
a highly conserved residue in the C-terminal region. The mutation was
not found in unaffected family members, in dbSNP v135, or in
approximately 3,200 alleles of the NHLBI Exome Sequencing Project.

In a 38-year-old female triathlete with dehydrated hereditary
stomatocytosis (DHS; 194380), Andolfo et al. (2013) identified
heterozygosity for the R2456H mutation in the PIEZO1 gene.

.0003
DEHYDRATED HEREDITARY STOMATOCYTOSIS AND PSEUDOHYPERKALEMIA
PIEZO1, ALA2020THR

In 14 affected members over 3 generations of a large French family with
dehydrated hereditary stomatocytosis and pseudohyperkalemia (DHS;
194380), previously studied by Grootenboer et al. (2000) (family 'VA')
and Beaurain et al. (2007), Albuisson et al. (2013) identified
heterozygosity for a point mutation in exon 42 of the PIEZO1 gene,
resulting in an ala2020-to-thr (A2020T) substitution at a highly
conserved residue in the C-terminal half of the protein. The mutation
was not found in 5 unaffected family members. Patch-clamp experiments in
transfected HEK293 cells demonstrated a considerable increase in the
inactivation time constant with the mutant compared to wildtype channel
kinetics, indicating that A2020T represents a gain-of-function mutation.
Affected members of this family presented with mild, uncomplicated
hematologic signs of DHS and pseudohyperkalemia, without a history of
perinatal edema.

.0004
DEHYDRATED HEREDITARY STOMATOCYTOSIS
PIEZO1, ARG1358PRO

In a French patient diagnosed at 69 years of age with dehydrated
hereditary stomatocytosis (DHS; 194380), Albuisson et al. (2013)
identified heterozygosity for a point mutation in exon 29 of the PIEZO1
gene, resulting in an arg1358-to-pro (R1358P) substitution at a highly
conserved residue in the C-terminal half of the protein. Patch-clamp
experiments in transfected HEK293 cells demonstrated a considerable
increase in the inactivation time constant with the mutant compared to
wildtype channel kinetics, indicating that R1358P represents a
gain-of-function mutation.

.0005
DEHYDRATED HEREDITARY STOMATOCYTOSIS AND PSEUDOHYPERKALEMIA
PIEZO1, THR2127MET

In a French man who was diagnosed at 65 years of age with dehydrated
hereditary stomatocytosis and pseudohyperkalemia (DHS; 194380), who was
previously studied by Syfuss et al. (2006) and had a history of
hepatosiderosis, Albuisson et al. (2013) identified heterozygosity for a
point mutation in exon 44 of the PIEZO1 gene, resulting in a
thr2127-to-met (T2127M) substitution at a highly conserved residue in
the C-terminal half of the protein. Patch-clamp experiments in
transfected HEK293 cells demonstrated a considerable increase in the
inactivation time constant with the mutant compared to wildtype channel
kinetics, indicating that T2127M represents a gain-of-function mutation.
The patient exhibited a moderate form of anemia and hemolysis without a
history of perinatal edema or initial evidence of pseudohyperkalemia.

In 13 affected members over 4 generations of a family from Edinburgh
with dehydrated hereditary stomatocytosis and pseudohyperkalemia,
originally reported by Stewart et al. (1979), Andolfo et al. (2013)
identified heterozygosity for the T2127M mutation in the PIEZO1 gene.
The mutation was not found in 8 unaffected family members or in 38
unrelated control exomes.

.0006
DEHYDRATED HEREDITARY STOMATOCYTOSIS
PIEZO1, 6-BP DUP, NT7479

In affected members of 2 French families with dehydrated hereditary
stomatocytosis (DHS; 194380), previously reported by Grootenboer et al.
(2000) (family 'VE') and Martinaud et al. (2008), respectively, and in 6
unrelated index DHS cases, Albuisson et al. (2013) identified
heterozygosity for an in-frame 6-bp duplication (c.7479_7484dupGGAGCT)
in exon 51 of the PIEZO1 gene, resulting in staggered in-frame
duplication of the respective residues (leu2945_glu2496dup), which the
authors designated E2496ELE. SNP analysis at the PIEZO1 gene showed that
the duplication was carried by at least 4 different haplotypes, thus
excluding an ancestral allele. The duplication segregated with disease
in the 2 families and was not found in the 1000 Genomes, Exome Variant
Server, or dbSNP v135 databases. However, E2496ELE was present in 2 of
600 healthy French controls, for a minor allele frequency of 0.0017;
Albuisson et al. (2013) noted that 1 of the 2 positive healthy
individuals had hyperkalemia in 1 of his blood tests, with no additional
information available. Patch-clamp experiments in transfected HEK293
cells demonstrated a considerable increase in the inactivation time
constant with the mutant compared to wildtype channel kinetics,
indicating that E2496ELE represents a gain-of-function mutation.

.0007
DEHYDRATED HEREDITARY STOMATOCYTOSIS
PIEZO1, SER1117LEU AND ALA2020VAL

In an Irish mother and son (family 'Essex') with dehydrated hereditary
stomatocytosis (DHS; 194380), originally reported by Carella et al.
(1998), Andolfo et al. (2013) identified heterozygosity for 2 in cis
missense mutations in the PIEZO1 gene: a c.3350C-T transition in exon
24, resulting in a ser1117-to-leu (S1117L) substitution, and a c.6059C-T
transition in exon 42, resulting in an ala2020-to-val (A2020V)
substitution. Patient red cells exhibited increased ion-channel
activity. Pseudohyperkalemia was not mentioned in the original report of
this family by Carella et al. (1998).

.0008
DEHYDRATED HEREDITARY STOMATOCYTOSIS WITH PSEUDOHYPERKALEMIA AND PERINATAL
EDEMA
PIEZO1, 1848+31C-G, GLY782SER, AND ARG808GLN

In a French Gypsy family with dehydrated hereditary stomatocytosis,
pseudohyperkalemia, and perinatal edema (DHS; 194380), originally
reported by Grootenboer et al. (1998) and later studied by Grootenboer
et al. (2000) as family 'BI,' Andolfo et al. (2013) identified
heterozygosity for 3 in cis mutations in the PIEZO1 gene: a 1848+31C-G
transversion in intron 14, and 2344G-A and 2423G-A transitions in exon
18, resulting in gly782-to-ser (G782S) and arg808-to-gln (R808Q)
substitutions, respectively, at conserved residues.

*FIELD* RF
1. Albuisson, J.; Murthy, S. E.; Bandell, M.; Coste, B.; Louis-dit-Picard,
H.; Mathur, J.; Feneant-Thibault, M.; Tertian, G.; de Jaureguiberry,
J.-P.; Syfuss, P.-Y.; Cahalan, S.; Garcon, L.; and 6 others: Dehydrated
hereditary stomatocytosis linked to gain-of-function mutations in
mechanically activated PIEZO1 ion channels. Nature Commun. 4: 1884,
2013. Note: Electronic Article.

2. Andolfo, I.; Alper, S. L.; De Franceschi, L.; Auriemma, C.; Russo,
R.; De Falco, L.; Vallefuoco, F.; Esposito, M. R.; Vandorpe, D. H.;
Shmukler, B. E.; Narayan, R.; Montanaro, D.; and 10 others: Multiple
clinical forms of dehydrated hereditary stomatocytosis arise from
mutations in PIEZO1. Blood 121: 3925-3935, 2013.

3. Beaurain, G.; Mathieu, F.; Grootenboer, S.; Fiquet, B.; Cynober,
T.; Tchernia, G.; Delaunay, J.; Jeunemaitre, X.: Dehydrated hereditary
stomatocytosis mimicking familial hyperkalaemic hypertension: clinical
and genetic investigation. Europ. J. Haemat. 78: 253-259, 2007.

4. Carella, M.; Stewart, G.; Ajetunmobi, J. F.; Perrotta, S.; Grootenboer,
S.; Tchernia, G.; Delaunay, J.; Totaro, A.; Zelante, L.; Gasparini,
P.; Iolascon, A.: Genomewide search for dehydrated hereditary stomatocytosis
(hereditary xerocytosis): mapping of locus to chromosome 16 (16q23-qter). Am.
J. Hum. Genet. 63: 810-816, 1998.

5. Coste, B.; Mathur, J.; Schmidt, M.; Earley, T. J.; Ranade, S.;
Petrus, M. J.; Dubin, A. E.; Patapoutian, A.: Piezo1 and Piezo2 are
essential components of distinct mechanically activated cation channels. Science 330:
55-60, 2010.

6. Coste, B.; Xiao, B.; Santos, J. S.; Syeda, R.; Grandl, J.; Spencer,
K. S.; Kim, S. E.; Schmidt, M.; Mathur, J.; Dubin, A. E.; Montal,
M.; Patapoutian, A.: Piezo proteins are pore-forming subunits of
mechanically activated channels. Nature 483: 176-181, 2012.

7. Grootenboer, S.; Schischmanoff, P.-O.; Laurendeau, I.; Cynober,
T.; Tchernia, G.; Dommergues, J.-P.; Dhermy, D.; Bost, M.; Varet,
B.; Snyder, M.; Ballas, S. K.; Ducot, B.; Babron, M.-C.; Stewart,
G. W.; Gasparini, P.; Iolascon, A.; Delaunay, J.: Pleiotropic syndrome
of dehydrated hereditary stomatocytosis, pseudohyperkalemia, and perinatal
edema maps to 16q23-q24. Blood 96: 2599-2605, 2000.

8. Grootenboer, S.; Schischmanoff, P. O.; Cynober, T.; Rodrigue, J.-C.;
Delaunay, J.; Tchernia, G.; Dommergues, J.-P.: A genetic syndrome
associating dehydrated hereditary stomatocytosis, pseudohyperkalaemia
and perinatal oedema. Brit. J. Haemat. 103: 383-386, 1998.

9. Houston, B. L.; Zelinski, T.; Israels, S. J.; Coghlan, G.; Chodirker,
B. N.; Gallagher, P. G.; Houston, D. S.; Zarychanski, R.: Refinement
of the hereditary xerocytosis locus on chromosome 16q in a large Canadian
kindred. Blood Cells Mol. Dis. 47: 226-231, 2011.

10. Kim, S. E.; Coste, B.; Chadha, A.; Cook, B.; Patapoutian, A.:
The role of Drosophila Piezo in mechanical nociception. Nature 483:
209-212, 2012.

11. Martinaud, C.; Gisserot, O.; Graffin, B.; Gaillard, T.; Brisou,
P.; Cynober, T.; de Jaureguiberry, J.-P.; Delaunay, J.; Aguilon, P.
: Antiphospholipid antibodies in a family with dehydrated hereditary
stomatocytosis. (Letter) Thromb. Res. 122: 572-575, 2008.

12. Miller, D. R.; Rickles, F. R.; Lichtman, M. A.; LaCelle, P. L.;
Bates, J.; Weed, R. I.: A new variant of hereditary hemolytic anemia
with stomatocytosis and erythrocyte cation abnormality. Blood 38:
184-203, 1971.

13. Nagase, T.; Seki, N.; Ishikawa, K.; Ohira, M.; Kawarabayasi, Y.;
Ohara, O.; Tanaka, A.; Kotani, H.; Miyajima, N.; Nomura, N.: Prediction
of the coding sequences of unidentified human genes. VI. The coding
sequences of 80 new genes (KIAA0201-KIAA0280) deduced by analysis
of cDNA clones from cell line KG-1 and brain. DNA Res. 3: 321-329,
1996. Note: Supplement: DNA Res. 3: 341-354, 1996.

14. Satoh, K.; Hata, M.; Takahara, S.; Tsuzaki, H.; Yokota, H.; Akatsu,
H.; Yamamoto, T.; Kosaka, K.; Yamada, T.: A novel membrane protein,
encoded by the gene covering KIAA0233, is transcriptionally induced
in senile plaque-associated astrocytes. Brain Res. 1108: 19-27,
2006.

15. Stewart, G. W.; Corrall, R. J. M.; Fyffe, J. A.; Stockdill, G.;
Strong, J. A.: Familial pseudohyperkalaemia: a new syndrome. Lancet 314:
175-177, 1979. Note: Originally Volume II.

16. Syfuss, P.-Y.; Ciupea, A.; Brahimi, S.; Cynober, T.; Stewart,
G. W.; Grandchamp, B.; Beaumont, C.; Tchernia, G.; Delaunay, J.; Wagner,
J.-C.: Mild dehydrated hereditary stomatocytosis revealed by marked
hepatosiderosis. Clin. Lab. Haemat. 28: 270-274, 2006.

17. Zarychanski, R.; Schulz, V. P.; Houston, B. L.; Maksimova, Y.;
Houston, D. S.; Smith, B.; Rinehart, J.; Gallagher, P. G.: Mutations
in the mechanotransduction protein PIEZO1 are associated with hereditary
xerocytosis. Blood 120: 1908-1915, 2012.

*FIELD* CN
Marla J. F. O'Neill - updated: 7/2/2013
Ada Hamosh - updated: 5/15/2012
Ada Hamosh - updated: 11/2/2010

*FIELD* CD
Dorothy S. Reilly: 7/10/2007

*FIELD* ED
carol: 10/15/2013
carol: 7/2/2013
alopez: 5/16/2012
terry: 5/15/2012
alopez: 11/16/2010
alopez: 11/8/2010
terry: 11/2/2010
alopez: 7/10/2007