2 research outputs found
Multiple clinical forms of dehydrated hereditary stomatocytosis arise from mutations in PIEZO1
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 CD341 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
Hypomorphic mutations of SEC23B gene account for mild phenotypes of congenital dyserythropoietic anemia type II
AbstractCongenital dyserythropoietic anemia type II, a recessive disorder of erythroid differentiation, is due to mutations in SEC23B, a component of the core trafficking machinery COPII. In no case homozygosity or compound heterozygosity for nonsense mutation(s) was found. This study represents the first description of molecular mechanisms underlying SEC23B hypomorphic genotypes by the analysis of five novel mutations. Our findings suggest that reduction of SEC23B gene expression is not associated with CDA II severe clinical presentation; conversely, the combination of a hypomorphic allele with one functionally altered results in more severe phenotypes. We propose a mechanism of compensation SEC23A-mediated which justifies these observations