• The mechanosensory ion channel Piezo1 is the carrier molecule for Er red cell antigens, establishing a new blood group system.

  • Antibodies directed against 2 novel high-incidence Er antigens are associated with severe hemolytic disease of the fetus and newborn.

Despite the identification of the high-incidence red cell antigen Era nearly 40 years ago, the molecular background of this antigen, together with the other 2 members of the Er blood group collection, has yet to be elucidated. Whole exome and Sanger sequencing of individuals with serologically defined Er alloantibodies identified several missense mutations within the PIEZO1 gene, encoding amino acid substitutions within the extracellular domain of the Piezo1 mechanosensor ion channel. Confirmation of Piezo1 as the carrier molecule for the Er blood group antigens was demonstrated using immunoprecipitation, CRISPR/Cas9-mediated gene knockout, and expression studies in an erythroblast cell line. We report the molecular bases of 5 Er blood group antigens: the recognized Era, Erb, and Er3 antigens and 2 novel high-incidence Er antigens, described here as Er4 and Er5, establishing a new blood group system. Anti-Er4 and anti-Er5 are implicated in severe hemolytic disease of the fetus and newborn. Demonstration of Piezo1, present at just a few hundred copies on the surface of the red blood cell, as the site of a new blood group system highlights the potential antigenicity of even low-abundance membrane proteins and contributes to our understanding of the in vivo characteristics of this important and widely studied protein in transfusion biology and beyond.

1.
International Society of Blood Transfusion (ISBT)
.
Red cell immunogenetics and blood group terminology
. Accessed 22 July 2022. https://www.isbtweb.org/working-parties/red-cell-immunogenetics-and-blood-group-terminology/.
2.
Daniels
GL
,
Judd
WJ
,
Moore
BP
, et al
.
A 'new' high frequency antigen Era
.
Transfusion
.
1982
;
22
(
3
):
189
-
193
.
3.
Hamilton
JR
,
Beattie
KM
,
Walker
RH
,
Hartrick
MB
.
Erb, an allele to Era, and evidence for a third allele, Er
.
Transfusion
.
1988
;
28
(
3
):
268
-
271
.
4.
Arriaga
F
,
Mueller
A
,
Rodberg
K
, et al
.
A new antigen of the Er collection
.
Vox Sang
.
2003
;
84
(
2
):
137
-
139
.
5.
Coste
B
,
Mathur
J
,
Schmidt
M
, et al
.
Piezo1 and Piezo2 are essential components of distinct mechanically activated cation channels
.
Science
.
2010
;
330
(
6000
):
55
-
60
.
6.
Coste
B
,
Xiao
B
,
Santos
JS
, et al
.
Piezo proteins are pore-forming subunits of mechanically activated channels
.
Nature
.
2012
;
483
(
7388
):
176
-
181
.
7.
Nagase
T
,
Seki
N
,
Ishikawa
K
, et al
.
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
.
1996
;
3
(
5
):
321
-
329
.
8.
Zhao
Q
,
Zhou
H
,
Chi
S
, et al
.
Structure and mechanogating mechanism of the Piezo1 channel
.
Nature
.
2018
;
554
(
7693
):
487
-
492
.
9.
Friedrich
EE
,
Hong
Z
,
Xiong
S
, et al
.
Endothelial cell Piezo1 mediates pressure-induced lung vascular hyperpermeability via disruption of adherens junctions
.
Proc Natl Acad Sci U S A
.
2019
;
116
(
26
):
12980
-
12985
.
10.
Dalghi
MG
,
Clayton
DR
,
Ruiz
WG
, et al
.
Expression and distribution of PIEZO1 in the mouse urinary tract
.
Am J Physiol Renal Physiol
.
2019
;
317
(
2
):
F303
-
F321
.
11.
Zhao
X
,
Kong
Y
,
Liang
B
, et al
.
Mechanosensitive Piezo1 channels mediate renal fibrosis
.
JCI Insight
.
2022
;
7
(
7
):
e152330
.
12.
Ranade
SS
,
Qiu
Z
,
Woo
SH
, et al
.
Piezo1, a mechanically activated ion channel, is required for vascular development in mice
.
Proc Natl Acad Sci U S A
.
2014
;
111
(
28
):
10347
-
10352
.
13.
Andolfo
I
,
Alper
SL
,
De Franceschi
L
, et al
.
Multiple clinical forms of dehydrated hereditary stomatocytosis arise from mutations in PIEZO1
.
Blood
.
2013
;
121
(
19
):
3925
-
3935
.
14.
Faucherre
A
,
Kissa
K
,
Nargeot
J
,
Mangoni
ME
,
Jopling
C
.
Piezo1 plays a role in erythrocyte volume homeostasis
.
Haematologica
.
2014
;
99
(
1
):
70
-
75
.
15.
Fotiou
E
,
Martin-Almedina
S
,
Simpson
MA
, et al
.
Novel mutations in PIEZO1 cause an autosomal recessive generalized lymphatic dysplasia with non-immune hydrops fetalis
.
Nat Commun
.
2015
;
6
:
8085
.
16.
Zarychanski
R
,
Schulz
VP
,
Houston
BL
, et al
.
Mutations in the mechanotransduction protein Piezo1 are associated with hereditary xerocytosis
.
Blood
.
2012
;
120
(
9
):
1908
-
1915
.
17.
Albuisson
J
,
Murthy
SE
,
Bandell
M
, et al
.
Dehydrated hereditary stomatocytosis linked to gain-of-function mutations in mechanically activated PIEZO1 ion channels
.
Nat Commun
.
2013
;
4
:
1884
.
18.
Kiger
L
,
Oliveira
L
,
Guitton
C
, et al
.
Piezo1-xerocytosis red cell metabolome shows impaired glycolysis and increased hemoglobin oxygen affinity
.
Blood Adv
.
2021
;
5
(
1
):
84
-
88
.
19.
Caulier
A
,
Jankovsky
N
,
Demont
Y
, et al
.
PIEZO1 activation delays erythroid differentiation of normal and hereditary xerocytosis-derived human progenitor cells
.
Haematologica
.
2020
;
105
(
3
):
610
-
622
.
20.
Moura
PL
,
Hawley
BR
,
Dobbe
JGG
, et al
.
PIEZO1 gain-of-function mutations delay reticulocyte maturation in hereditary xerocytosis
.
Haematologica
.
2020
;
105
(
6
):
e268
-
e271
.
21.
Ma
S
,
Dubin
AE
,
Zhang
Y
, et al
.
A role of PIEZO1 in iron metabolism in mice and humans
.
Cell
.
2021
;
184
(
4
):
969
-
982.e13
.
22.
Beneteau
C
,
Thierry
G
,
Blesson
S
, et al
.
Recurrent mutation in the PIEZO1 gene in two families of hereditary xerocytosis with fetal hydrops
.
Clin Genet
.
2014
;
85
(
3
):
293
-
295
.
23.
Martin-Almedina
S
,
Mansour
S
,
Ostergaard
P
.
Human phenotypes caused by PIEZO1 mutations; one gene, two overlapping phenotypes?
.
J Physiol
.
2018
;
596
(
6
):
985
-
992
.
24.
Omasits
U
,
Ahrens
CH
,
Müller
S
,
Wollscheid
B
.
Protter: interactive protein feature visualization and integration with experimental proteomic data
.
Bioinformatics
.
2014
;
30
(
6
):
884
-
886
.
25.
Cahalan
SM
,
Lukacs
V
,
Ranade
SS
,
Chien
S
,
Bandell
M
,
Patapoutian
A
.
Piezo1 links mechanical forces to red blood cell volume
.
Elife
.
2015
;
4
:
e07370
.
26.
Gautier
EF
,
Leduc
M
,
Cochet
S
, et al
.
Absolute proteome quantification of highly purified populations of circulating reticulocytes and mature erythrocytes
.
Blood Adv
.
2018
;
2
(
20
):
2646
-
2657
.
27.
Thorvaldsdóttir
H
,
Robinson
JT
,
Mesirov
JP
.
Integrative Genomics Viewer (IGV): high-performance genomics data visualization and exploration
.
Brief Bioinform
.
2013
;
14
(
2
):
178
-
192
.
28.
Trakarnsanga
K
,
Griffiths
RE
,
Wilson
MC
, et al
.
An immortalized adult human erythroid line facilitates sustainable and scalable generation of functional red cells
.
Nat Commun
.
2017
;
8
:
14750
.
29.
Hawksworth
J
,
Satchwell
TJ
,
Meinders
M
, et al
.
Enhancement of red blood cell transfusion compatibility using CRISPR-mediated erythroblast gene editing
.
EMBO Mol Med
.
2018
;
10
(
6
):
e8454
.
30.
Syeda
R
,
Xu
J
,
Dubin
AE
, et al
.
Chemical activation of the mechanotransduction channel Piezo1
.
Elife
.
2015
;
4
:
e07369
.
31.
Spring
FA
,
Reid
ME
.
Evidence that the human blood group antigens Gya and Hy are carried on a novel glycosylphosphatidylinositol-linked erythrocyte membrane glycoprotein
.
Vox Sang
.
1991
;
60
(
1
):
53
-
59
.
32.
Rotordam
MG
,
Fermo
E
,
Becker
N
, et al
.
A novel gain-of-function mutation of Piezo1 is functionally affirmed in red blood cells by high-throughput patch clamp
.
Haematologica
.
2019
;
104
(
5
):
e179
-
e183
.
33.
Waterhouse
A
,
Bertoni
M
,
Bienert
S
, et al
.
SWISS-MODEL: homology modelling of protein structures and complexes
.
Nucleic Acids Res
.
2018
;
46
(
W1
):
W296
-
W303
.
34.
Kaufman
HW
,
Niles
JK
,
Gallagher
DR
, et al
.
Revised prevalence estimate of possible hereditary xerocytosis as derived from a large U.S. laboratory database
.
Am J Hematol
.
2018
;
93
(
1
):
E9
-
E12
.
35.
Miller
DR
,
Rickles
FR
,
Lichtman
MA
,
La Celle
PL
,
Bates
J
,
Weed
RI
.
A new variant of hereditary hemolytic anemia with stomatocytosis and erythrocyte cation abnormality
.
Blood
.
1971
;
38
(
2
):
184
-
204
.
36.
Russo
R
,
Andolfo
I
,
Manna
F
, et al
.
Multi-gene panel testing improves diagnosis and management of patients with hereditary anemias
.
Am J Hematol
.
2018
;
93
(
5
):
672
-
682
.
37.
Andolfo
I
,
Russo
R
,
Rosato
BE
, et al
.
Genotype-phenotype correlation and risk stratification in a cohort of 123 hereditary stomatocytosis patients
.
Am J Hematol
.
2018
;
93
(
12
):
1509
-
1517
.
38.
Andolfo
I
,
Martone
S
,
Rosato
BE
, et al
.
Complex modes of inheritance in hereditary red blood cell disorders: a case series study of 155 patients
.
Genes (Basel)
.
2021
;
12
(
7
):
958
.
39.
Thye
T
,
Evans
JA
,
Ruge
G
, et al
.
Human genetic variant E756del in the ion channel PIEZO1 not associated with protection from severe malaria in a large Ghanaian study
.
J Hum Genet
.
2022
;
67
(
1
):
65
-
67
.
40.
Ma
S
,
Cahalan
S
,
LaMonte
G
, et al
.
Common PIEZO1 allele in African populations causes RBC dehydration and attenuates Plasmodium infection
.
Cell
.
2018
;
173
(
2
):
443
-
455
.
41.
Nguetse
CN
,
Purington
N
,
Ebel
ER
, et al
.
A common polymorphism in the mechanosensitive ion channel PIEZO1 is associated with protection from severe malaria in humans
.
Proc Natl Acad Sci U S A
.
2020
;
117
(
16
):
9074
-
9081
.
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