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Aberrant Membrane Composition and Biophysical Properties Impair Erythrocyte Morphology and Functionality in Elliptocytosis
Red blood cell (RBC) deformability is altered in inherited RBC disorders but the mechanism behind this is poorly understood. Here, we explored the molecular, biophysical, morphological, and functional consequences of α-spectrin mutations in a patient with hereditary elliptocytosis (pEl) almost exclu...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7465299/ https://www.ncbi.nlm.nih.gov/pubmed/32751168 http://dx.doi.org/10.3390/biom10081120 |
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author | Pollet, Hélène Cloos, Anne-Sophie Stommen, Amaury Vanderroost, Juliette Conrard, Louise Paquot, Adrien Ghodsi, Marine Carquin, Mélanie Léonard, Catherine Guthmann, Manuel Lingurski, Maxime Vermylen, Christiane Killian, Theodore Gatto, Laurent Rider, Mark Pyr dit Ruys, Sébastien Vertommen, Didier Vikkula, Miikka Brouillard, Pascal Van Der Smissen, Patrick Muccioli, Giulio G. Tyteca, Donatienne |
author_facet | Pollet, Hélène Cloos, Anne-Sophie Stommen, Amaury Vanderroost, Juliette Conrard, Louise Paquot, Adrien Ghodsi, Marine Carquin, Mélanie Léonard, Catherine Guthmann, Manuel Lingurski, Maxime Vermylen, Christiane Killian, Theodore Gatto, Laurent Rider, Mark Pyr dit Ruys, Sébastien Vertommen, Didier Vikkula, Miikka Brouillard, Pascal Van Der Smissen, Patrick Muccioli, Giulio G. Tyteca, Donatienne |
author_sort | Pollet, Hélène |
collection | PubMed |
description | Red blood cell (RBC) deformability is altered in inherited RBC disorders but the mechanism behind this is poorly understood. Here, we explored the molecular, biophysical, morphological, and functional consequences of α-spectrin mutations in a patient with hereditary elliptocytosis (pEl) almost exclusively expressing the Pro260 variant of SPTA1 and her mother (pElm), heterozygous for this mutation. At the molecular level, the pEI RBC proteome was globally preserved but spectrin density at cell edges was increased. Decreased phosphatidylserine vs. increased lysophosphatidylserine species, and enhanced lipid peroxidation, methemoglobin, and plasma acid sphingomyelinase (aSMase) activity were observed. At the biophysical level, although membrane transversal asymmetry was preserved, curvature at RBC edges and rigidity were increased. Lipid domains were altered for membrane:cytoskeleton anchorage, cholesterol content and response to Ca(2+) exchange stimulation. At the morphological and functional levels, pEl RBCs exhibited reduced size and circularity, increased fragility and impaired membrane Ca(2+) exchanges. The contribution of increased membrane curvature to the pEl phenotype was shown by mechanistic experiments in healthy RBCs upon lysophosphatidylserine membrane insertion. The role of lipid domain defects was proved by cholesterol depletion and aSMase inhibition in pEl. The data indicate that aberrant membrane content and biophysical properties alter pEl RBC morphology and functionality. |
format | Online Article Text |
id | pubmed-7465299 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-74652992020-09-04 Aberrant Membrane Composition and Biophysical Properties Impair Erythrocyte Morphology and Functionality in Elliptocytosis Pollet, Hélène Cloos, Anne-Sophie Stommen, Amaury Vanderroost, Juliette Conrard, Louise Paquot, Adrien Ghodsi, Marine Carquin, Mélanie Léonard, Catherine Guthmann, Manuel Lingurski, Maxime Vermylen, Christiane Killian, Theodore Gatto, Laurent Rider, Mark Pyr dit Ruys, Sébastien Vertommen, Didier Vikkula, Miikka Brouillard, Pascal Van Der Smissen, Patrick Muccioli, Giulio G. Tyteca, Donatienne Biomolecules Article Red blood cell (RBC) deformability is altered in inherited RBC disorders but the mechanism behind this is poorly understood. Here, we explored the molecular, biophysical, morphological, and functional consequences of α-spectrin mutations in a patient with hereditary elliptocytosis (pEl) almost exclusively expressing the Pro260 variant of SPTA1 and her mother (pElm), heterozygous for this mutation. At the molecular level, the pEI RBC proteome was globally preserved but spectrin density at cell edges was increased. Decreased phosphatidylserine vs. increased lysophosphatidylserine species, and enhanced lipid peroxidation, methemoglobin, and plasma acid sphingomyelinase (aSMase) activity were observed. At the biophysical level, although membrane transversal asymmetry was preserved, curvature at RBC edges and rigidity were increased. Lipid domains were altered for membrane:cytoskeleton anchorage, cholesterol content and response to Ca(2+) exchange stimulation. At the morphological and functional levels, pEl RBCs exhibited reduced size and circularity, increased fragility and impaired membrane Ca(2+) exchanges. The contribution of increased membrane curvature to the pEl phenotype was shown by mechanistic experiments in healthy RBCs upon lysophosphatidylserine membrane insertion. The role of lipid domain defects was proved by cholesterol depletion and aSMase inhibition in pEl. The data indicate that aberrant membrane content and biophysical properties alter pEl RBC morphology and functionality. MDPI 2020-07-29 /pmc/articles/PMC7465299/ /pubmed/32751168 http://dx.doi.org/10.3390/biom10081120 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Pollet, Hélène Cloos, Anne-Sophie Stommen, Amaury Vanderroost, Juliette Conrard, Louise Paquot, Adrien Ghodsi, Marine Carquin, Mélanie Léonard, Catherine Guthmann, Manuel Lingurski, Maxime Vermylen, Christiane Killian, Theodore Gatto, Laurent Rider, Mark Pyr dit Ruys, Sébastien Vertommen, Didier Vikkula, Miikka Brouillard, Pascal Van Der Smissen, Patrick Muccioli, Giulio G. Tyteca, Donatienne Aberrant Membrane Composition and Biophysical Properties Impair Erythrocyte Morphology and Functionality in Elliptocytosis |
title | Aberrant Membrane Composition and Biophysical Properties Impair Erythrocyte Morphology and Functionality in Elliptocytosis |
title_full | Aberrant Membrane Composition and Biophysical Properties Impair Erythrocyte Morphology and Functionality in Elliptocytosis |
title_fullStr | Aberrant Membrane Composition and Biophysical Properties Impair Erythrocyte Morphology and Functionality in Elliptocytosis |
title_full_unstemmed | Aberrant Membrane Composition and Biophysical Properties Impair Erythrocyte Morphology and Functionality in Elliptocytosis |
title_short | Aberrant Membrane Composition and Biophysical Properties Impair Erythrocyte Morphology and Functionality in Elliptocytosis |
title_sort | aberrant membrane composition and biophysical properties impair erythrocyte morphology and functionality in elliptocytosis |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7465299/ https://www.ncbi.nlm.nih.gov/pubmed/32751168 http://dx.doi.org/10.3390/biom10081120 |
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