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Blood, 15 December 2005, Vol. 106, No. 13, pp. 4024-4025.
Band 3 "Neapolis": ciao ciao aldolaseCHILDREN'S HOSPITAL BOSTON
The N-terminal region of protein band 3 plays an important role in associating several cytoplasmic proteins with the red cell membrane. Perrotta and colleagues have identified a novel band 3 mutation, "Neapolis," which causes severe hemolytic anemia, does not bind aldolase, and cannot be tyrosine phosphorylated.
In this issue of Blood, Perrotta and colleagues report a novel band 3 mutation (Neapolis) that they identified in a child affected by severe transfusion-dependent microspherocytic hemolytic anemia and that was improved by splenectomy. Both parents had mild HS. Band 3 Neapolis is characterized by absence of the first 11 amino acids (aa) at the N-terminal portion of the wild-type polypeptide. This mutation results in complete loss of the red cell membrane's ability to bind the key glycolytic enzyme, aldolase, likely due to the loss of its binding site on the band 3 N-terminal peptide missing from band 3 Neapolis. There is almost no phosphorylation of band 3 Neapolis in intact red cells, due to the loss of a critical tyrosine in position 8. In addition, the ability of Plasmodium falciparum to invade and mature in band 3 Neapolis erythrocytes is markedly diminished.
As with other band 3 mutations, the relative role of cytoskeletal abnormalities and functional/regulatory abnormalities in producing premature destruction of red cells is still not entirely clear. The severely reduced level of band 3 Neapolis in the red cell membrane of the homozygous child (only References
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| Copyright © 2005 by American Society of Hematology Online ISSN: 1528-0020 | |||||||||
12% of the normal number) is the most likely determinant of the cytoskeletal disease and associated spherocytic hemolytic anemia. This is supported by the substantial clinical improvement seen in this patient after splenectomy. It will be more difficult to tease out the effects on red cell function specifically attributable to the altered binding of aldolase to band 3. However, this patient may offer the possibility of testing definitively the physiologic relevance of these protein-binding interactions often debated in the past. The functional consequences of the inability to phosphorylate band 3 Neapolis by treatment of intact cells with the sulfhydryl oxidizing agent, diamide, remain uncertain, as is the relationship of this altered phosphorylation to the relative resistance of these cells to malaria infection. However, this exciting report demonstrates one more time the incredible multifunctional complexity of protein band 3, as key an ingredient for producing a normal red cell as tomatoes are to a perfect Neapolitan pizza.