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 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.

Hypomorphic mutations of SEC23B gene account for mild phenotypes of congenital dyserythropoietic anemia type II.

Congenital 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.

Trasferrin receptor 2 gene regulation by microRNA 221 in SH-SY5Y cells treated with MPP⁺ as Parkinson's disease cellular model.

Parkinson's disease (PD) is one of the most frequent human neurodegenerations. The neurodegeneration in PD is related to cellular iron increase but the mechanisms involved in iron accumulation remain unclear. Transferrin receptor type 2 (TFR2) is a protein expressed on cell membrane and involved in the cellular iron uptake. We hypothesized that microRNA 221 could regulate the expression of TfR2 in an in vitro model of Parkinson's disease, SH-SY5Y cells treated with MPP⁺. The miRNA 221 was selected by in silico analysis of several miRNAs predicted to target the TFR2 gene in SHSY5Y cells treated with MPP⁺. Taqman miRNA assay was used to evaluate the expression of the selected miRNAs. Using a luciferase assay we demonstrated the inhibition of TFR2 by miRNA 221. We show that in PD cellular model, TFR2 expression is regulated by miRNA 221. TFR2 and miR 221 are inversely correlated in SHSY5Y cells during the treatment with MPP⁺. Moreover, overexpression of miRNA 221 decreases the expression of TFR2, respectively, at the mRNA and protein levels. The inhibition of endogenous miRNA 221 also is able to regulate TFR2. These data suggest that miRNA 221 regulate TFR2 in PD model.