Heterogeneous phenotype of Hereditary Xerocytosis in association with PIEZO1 variants
| Autor: | Murilo Castro Cervato, Roberta Sitnik, Sandra Fátima Menosi Gualandro, João Renato Rebello Pinho, Narla Mohandas, Paulo Augusto Achucarro Silveira, Nair Hideko Muto, Liliana Mitie Suganuma, Andrea Balan, Guilherme Henrique Hencklain Fonseca, Priscila de Meira Oliveira |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Adult Male Protein Conformation alpha-Helical Adolescent Hydrops Fetalis Mutation Missense Biology Anemia Hemolytic Congenital Ion Channels 03 medical and health sciences Mice 0302 clinical medicine Mechanosensitive ion channel Protein Domains Gene duplication medicine Missense mutation Animals Humans Child Molecular Biology Genetics PIEZO1 Infant Newborn Cell Biology Hematology Middle Aged medicine.disease Phenotype Transmembrane domain 030104 developmental biology Amino Acid Substitution Molecular Medicine Mechanosensitive channels Female Congenital hemolytic anemia 030215 immunology |
| Zdroj: | Blood cells, moleculesdiseases. 82 |
| ISSN: | 1096-0961 |
| Popis: | Hereditary Xerocytosis (HX) is an autosomal dominantly inherited congenital hemolytic anemia associated with erythrocyte dehydration due to decreased intracellular potassium content resulting in increased mean corpuscular hemoglobin concentration. The affected members of HX families show compensated anemia with splenomegaly, hemosiderosis, and perinatal edema but are in large part transfusion independent. Functional studies show a link between mutations in mechanosensitive ion channel, encoded by PIEZO1 gene and the HX. We identified new PIEZO1 variants that are likely pathogenic in three phenotypically characterized multi-generational HX Brazilian families. Interestingly, one missense variant of the PIEZO1 gene identified, p.E2494V was associated in trans with the previously reported most frequent pathogenic duplication p.E2496ELE. The three-dimensional structure of the human protein modeled using structural coordinates of the mouse Piezo1 solved by cryo-electron microscopy (Cryo-ME) showed that the two identified variants, p.M2007L and p.T2014I, are localized to an important mechanosensitive transmembrane domain suggesting a conformational mechanism for altered channel's gating. The p.E2496ELE variant identified alters the extension of helix α1 bringing it much closer to the beam affecting the position of it structure at the end of the pore. |
| Databáze: | OpenAIRE |
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