New insights on hereditary erythrocyte membrane defects

Abstract

© Ferrata Storti Foundationmary role in the removal of aged RBCs. In order to perform these journeys RBCs must possess and maintain a significant deformability. The main author of this property is certainly the membrane, that ensures both mechanical stability and deformability. After the first proposed model of the RBC membrane skeleton 36 years ago, 1 containing the core elements of the modern model, many additional proteins have been discovered during the intervening decades, and their structures and interactions have been defined. RBC membrane structure has been extensively covered by excellent reviews.2,3 Herein we summarize the main concepts. RBC membrane is composed by a fluid double layer of lipids in which approximately 20 major proteins and at least 850 minor ones are embedded. 4 The membrane is attached to an intracellular cytoskeleton by protein-protein and lipid-protein interactions that confer the erythrocyte shape, stability and deformability. The transmembrane proteins have mainly a transporter function. However, several of these also have a structural function, usually performed by an intracytoplasmic domain interacting with cytoskeletal proteins.The lipid bilayer acts as a barrier for the retention of cations and anions within the red cells, while it allows water molecules to pass through freely. Human erythrocytes have high intracellular K + and low intracellular Na + contents when compared with the corresponding ion concentrations in the plasma. The maintenance of this cation gradient between the cell and its environment involves a passive outward movement of K + , which is pumped back by the action of an ATP-dependent Na + /K + pump in exchange for Na+ ions. This protein belongs to a class of transmembrane proteins with a transport function (Figure 1). The third and more important component of the RBC membrane is the cytoskeleton, a protein network that laminates the inner surface of the membrane. Spectrin aand β-chains, proteins 4.1, or 4.1R, and actin are the main components of this skeleton, maintaining the biconcave shape of the RBC. These components are connected to each other in two protein complexes; ankyrin and protein 4.1 complex. The former is composed by band 3 tetramers, Rh, RhAG, CD47, glycophorin A and protein 4.2. Whereas the protein 4.1 complex is composed by band 3 dimers binding adducins a-and β-, glycophorin C, GLUT1 and stomatin (Figure 1). The ends of spectrin tetramers converge toward a protein 4.1 complex (junctional complex). Electron microscopy (EM) shows that this latter links the tail of six spectrin tetramers, forming a pseudo-hexagonal arrangement. 5Spectrin tetramers include anion transporters (band 3 or chloride/bicarbonate exchange). The capability of these transporters to form aggregates could define the half-life of RBCs, causing antibody binding and removal by the spleen. Defects that interrupt this vertical structure (spectrin-actin interaction) underlie the biochemical and molecular basis of hereditary spherocytosis (HS), whereas defects in horizo...

Osmotic gradient ektacytometry: A valuable screening test for hereditary spherocytosis and other red blood cell membrane disorders

“…Main RBC membrane disorders, namely hereditary spherocytosis (HS), hereditary elliptocytosis (HE), and hereditary stomatocytosis (HSt), alter membrane cohesion, membrane mechanical stability, and RBC volume, respectively. As a consequence, RBC deformability is compromised leading to their premature removal from circulation by the spleen, manifested as hemolytic anemia …”

“…As a consequence, RBC deformability is compromised leading to their premature removal from circulation by the spleen, manifested as hemolytic anemia. [5][6][7][8] HS and HE are RBC membrane disorders characterized by mutations in genes encoding membrane or skeletal proteins respectively, and its mutations alter the membrane complex structure. HS is the most common inherited RBC membrane disorder with one case of 2000 individuals in the Northern European countries, and probably even higher prevalence due to under diagnosis of minor or even moderate forms.…”

Targeted mutation screening of 292 candidate genes in 38 children with inborn haematological cytopenias efficiently identifies novel disease‐causing mutations

“…Two patients with mild macrocytic anaemia had mutations in the gene encoding the piezo‐type mechanosensitive ion channel component 1 ( PIEZO1 ) : Patient 7 bore a previously described pathogenic p.R2456H variant (Zarychanski et al , ), and Patient 8 a novel p.Q1361R mutation located adjacent to the already known p.R1358P mutation (Table ) (Albuisson et al , ). This finding, together with the subsequent perception of dessicytes in the respective blood smears (Fig B,C) was particularly relevant, given that splenectomy had been considered prior to identifying the disease as hereditary xerocytosis (HX); this form of treatment is contraindicated in HX because of an associated inherent increased risk of thromboembolic complications (Andolfo et al , ). In Patients 9 and 10, novel compound heterozygous mutations in codanin 1 ( CDAN1 ) confirmed the respective diagnosis of CDA type 1 (CDA1), which originally had solely been based on the morphological abnormalities of erythropoietic components in the peripheral blood and bone marrow (Fig D–F; Table ).…”

PIEZO1-R1864H rare variant accounts for a genetic phenotype-modifier role in dehydrated hereditary stomatocytosis

“…They may present severe iron overload leading to hepatic transplantation, or life threatening thromboembolic disease after splenectomy, thus making the diagnosis of this condition very tricky. 1 DHS results in two different forms: (i) DHS1, the most frequent, is caused by mutations in PIEZO1, encoding a cation selective channel activated by mechanical force; (ii) DHS2…”