IntroductionThe congenital dyserythropoietic anemias (CDAs) comprise a group of rare hereditary disorders of erythropoiesis, characterized by ineffective erythropoiesis as the predominant mechanism of anemia and by distinct morphologic abnormalities of the majority of erythroblasts in the bone marrow. The term was first used by Crookston et al 1 (for cases later classified as CDA II) and by Wendt and Heimpel 2 (for cases later classified as CDA I), but a few reports of similar cases had been published previously. 3 In 1968, we proposed classifying these disorders into 3 types. 3 Although initially proposed as a working classification, it was widely accepted and is still used today in clinical practice. 4,5 CDA II, also known as hereditary erythroblastic multinuclearity with a positive acidified-serum test (HEMPAS), 6 is the most frequently encountered disorder of the CDA group. 4,5,7,8 The leading morphologic abnormality is binuclearity or multinuclearity occurring in 10% to 50% of mature erythroblasts, with equal DNA content in both nuclei. 9 Electron microscopy (EM) shows a double membrane close to the cell membrane of mature erythroid cells, 10 which is due to residual endoplasmic reticulum. 11 Band 3 appears thinner and shows faster migration on sodium dodecyl sulfatepolyacrylamide gel electrophoresis (SDS-PAGE). 12 Red cells of patients with CDA II retain throughout life a very high agglutinability by anti-i sera. 6 The abnormalities of the CDA II red blood cell membrane are due to abnormal processing of N-glycans. 13 Band 3 and band 4.5 glycoproteins carry truncated polylactosamine structures, while glycolipids are sometimes overglycosylated. 14 An association to a gene locus on chromosome 20 (q11.2) was described in families from Southern Italy. 7,15 After our description of the first families in 1968, 3,16 we observed many more cases, mostly in residents of Germany, but also from Austria, Switzerland, and the Czech Republic, and we were able to follow some patients up to 35 years. Data from these patients as well as from case reports in the literature were collected in the German CDA registry, set up in 1993. Here we report epidemiologic data, clinical manifestations, and diagnostic features of 48 patients with CDA II. Particular emphasis is given to the course of the disease as a basis for management of these patients. Patients, materials, and methodsDiagnosis of CDA II was based on the criteria shown in Table 1. Data were extracted from files of the institutions and physicians responsible for patients' management from 1950 to 2002, in addition to the personal observations of one of the authors (H.H.) from the university hospitals of Freiburg and Ulm, Germany. Informed consent was obtained for additional blood samples taken for research objectives. A code identifying the family, the cases, and their relatives was assigned to each individual. Family trees were constructed by Cyrillic 2.1.2 (Cherwell Scientific Publishing, Oxford, United Kingdom). Data from 14 patients from 11 families had been published ...
Hereditary spherocytosis (HS) is a common hemolytic anemia of variable clinical expression. Pathogenesis of HS has been associated with defects of several red cell membrane proteins including erythroid band 3. We have studied erythrocyte membrane proteins in 166 families with autosomal dominant HS. We have detected relative deficiency of band 3 in 38 kindred (23%). Band 3 deficiency was invariably associated with mild autosomal dominant spherocytosis and with the presence of pincered red cells in the peripheral blood smears of unsplenectomized patients. We hypothesized that this phenotype is caused by band 3 gene defects. Therefore, we screened band 3 DNA from these 38 kindred for single strand conformational polymorphisms (SSCP). In addition to five mutations detected previously by SSCP screening of cDNA, we detected 13 new band 3 gene mutations in 14 kindred coinherited with HS. These novel mutations consisted of two distinct subsets. The first subset included seven nonsense and frameshift mutations that were all associated with the absence of the mutant mRNA allele from reticulocyte RNA, implicating decreased production and/or stability of mutant mRNA as the cause of decreased band 3 synthesis. The second group included five substitutions of highly conserved amino acids and one in-frame deletion. These six mutations were associated with the presence of comparable levels of normal and mutant band 3 mRNA. We suggest that these mutations interfere with band 3 biosynthesis leading thus to the decreased accumulation of the mutant band 3 allele in the plasma membrane.
To elucidate the molecular basis of band 3 deficiency in a recently defined subset of patients with autosomal dominant hereditary spherocytosis (HS), we screened band 3 cDNA for single-strand conformation polymorphism (SSCP). In 5 of 17 (29%) unrelated HS subjects with band 3 deficiency, we detected substitutions R760W, R760Q, R808C, and R870W that were all coinherited with the HS phenotype. The involved arginines are highly conserved throughout evolution. To examine whether or not the product of the mutant allele is inserted into the membrane, we studied one HS subject who was doubly heterozygous for the R760Q mutation and the K56E (band 3sMEMPHIS) polymorphism that results in altered electrophoretic mobility of the band 3 Memphis proteolytic fragments. We detected only the band 3MEMPHIS in the erythrocyte membrane indicating that the protein product of the mutant, R760Q, band 3 allele is absent from the red blood cell membrane. These findings suggest that the R760Q substitution, and probably the other arginine subsitutions, produce band 3 deficiency either by precluding incorporation of the mutant protein into the red blood cell membrane or by leading to loss of mutant protein from differentiating erythroid precursors.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.