Rosato, Barbara Eleni (2021) Unraveling the molecular basis of iron overload in rare hereditary anemias: Dehydrated hereditary stomatocytosis and Congenital dyserythropoietic anemia type II. [Tesi di dottorato]


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Item Type: Tesi di dottorato
Resource language: English
Title: Unraveling the molecular basis of iron overload in rare hereditary anemias: Dehydrated hereditary stomatocytosis and Congenital dyserythropoietic anemia type II
Rosato, Barbara
Date: 7 April 2021
Number of Pages: 99
Institution: Università degli Studi di Napoli Federico II
Department: Medicina Molecolare e Biotecnologie Mediche
Dottorato: Medicina molecolare e biotecnologie mediche
Ciclo di dottorato: 33
Coordinatore del Corso di dottorato:
Iolascon, AchilleUNSPECIFIED
Date: 7 April 2021
Number of Pages: 99
Keywords: iron overload, Congenital dyserythropoietic anemia, Dehydrated hereditary stomatocytosis
Settori scientifico-disciplinari del MIUR: Area 06 - Scienze mediche > MED/03 - Genetica medica
Date Deposited: 20 Apr 2021 08:00
Last Modified: 07 Jun 2023 10:34

Collection description

Hereditary anemias are a large group of disorders caused by alterations in genes involved in hemoglobin production, erythropoiesis and red cell structure and metabolism. Among them we focused on: Dehydrated hereditary stomatocytosis (DHS) and congenital dyserythropoietic anemia type II (CDAII). DHS is an autosomal dominant anemia characterized by altered intracellular cation content and cell volume alterations caused by gain of function mutations in PIEZO1, a mechanoreceptor activated by various types of mechanical stimuli. CDAII is an autosomal recessive anemia characterized by the impairment of erythroid differentiation and ineffective erythropoiesis. The causative gene of this condition, SEC23B, encodes for the homonymous member of the COPII complex, involved in the secretory pathway of eukaryotic cell and that mediates anterograde transport of correctly folded cargo from the endoplasmic reticulum toward the Golgi apparatus. Although patients affected by DHS and CDAII exhibit different phenotypes, they share the strong tendency to hepatic iron overload that represents the most harmful complication in both conditions. Iron overload in DHS patients has already reported to be independent from the degree of anemia, as confirmed by plasma levels of ERFE, the only known erythroid regulator of HAMP gene expression. Intriguingly, despite the dyserythropoietic component, we observed that ERFE concentration was almost unvaried in CDAII patients with mild anemia compared to more severely affected patients. These findings suggested that a specific involvement of the two genes at hepatic level could determine the iron overload. We demonstrated that their alteration accounts for a deregulation of BMP/SMAD pathway although through different mechanisms. Particularly, in PIEZO1 mutated cells (both transient overexpressing model and engineered cells) the increased intracellular calcium concentration leads to deregulation of MAP Kinase pathway that in turns regulates the SMADs expression (at both protein and mRNA levels) resulting in HAMP suppression. As proof of the specific PIEZO1 involvement, the selective inhibition of the mechanoreceptor by GsMTx-4, completely rescued the cellular phenotype observed, restoring the HAMP gene transcription. On the other hand, we demonstrated that SEC23B loss of function at hepatic level altered the glycosylation, as already found in erythrocytes, of membrane proteins involved in BMP/SMADs pathway activation. Cells silenced for SEC23B showed a reduced ability to sense BMP-6 mediated stimulus leading to a reduced expression of hepcidin. Understanding the molecular mechanism that underlie hepatic iron overload will be useful to draw up new therapeutic options for these patients.


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