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Aberrant Membrane Composition and Biophysical Properties Impair Erythrocyte Morphology and Functionality in Elliptocytosis.
Biomolecules ( IF 5.5 ) Pub Date : 2020-07-29 , DOI: 10.3390/biom10081120
Hélène Pollet 1 , Anne-Sophie Cloos 1 , Amaury Stommen 1 , Juliette Vanderroost 1 , Louise Conrard 1 , Adrien Paquot 2 , Marine Ghodsi 1 , Mélanie Carquin 1 , Catherine Léonard 1 , Manuel Guthmann 1 , Maxime Lingurski 1 , Christiane Vermylen 3 , Theodore Killian 4 , Laurent Gatto 4 , Mark Rider 5 , Sébastien Pyr Dit Ruys 5 , Didier Vertommen 5 , Miikka Vikkula 6, 7 , Pascal Brouillard 6 , Patrick Van Der Smissen 1 , Giulio G Muccioli 2 , Donatienne Tyteca 1
Affiliation  

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 Ca2+ exchange stimulation. At the morphological and functional levels, pEl RBCs exhibited reduced size and circularity, increased fragility and impaired membrane Ca2+ 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.

中文翻译:

异常的膜成分和生物物理特性会损害红细胞形态和功能。

在遗传的RBC疾病中,红细胞(RBC)的可变形性发生了改变,但是其背后的机制却鲜为人知。在这里,我们探讨了遗传性细胞增多症(pEl)患者中α-血影蛋白突变的分子,生物物理,形态和功能后果,该患者几乎仅表达SPTA1的Pro260变体和她的母亲(pElm),该突变为杂合性。在分子水平上,pEI RBC蛋白质组被全局保存,但细胞边缘的血影蛋白密度增加。与增加的溶血磷脂酰丝氨酸种类相比,磷脂酰丝氨酸减少,并且脂质过氧化,高铁血红蛋白和血浆酸鞘磷脂酶(aSMase)活性增强。在生物物理水平上,尽管膜横向不对称得以保留,但RBC边缘的曲率和刚度却增加了。2+交流刺激。在形态和功能水平上,pEl RBCs表现出减小的尺寸和圆形度,增加的脆性和受损的Ca 2+交换。在健康的红细胞中,通过溶血磷脂酰丝氨酸膜插入后的机械实验显示了膜曲率增加对pEl表型的贡献。pEl中的胆固醇消耗和aSMase抑制作用证明了脂质结构域缺陷的作用。数据表明异常的膜含量和生物物理性质改变了pEl RBC的形态和功能。
更新日期:2020-07-29
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