Clinical aspects and pathogenesis of congenital dyserythropoietic anemias: from morphology to molecular approach

Abstract

Congenital dyserythropoietic anemias belong to a group of inherited conditions characterized by a maturation arrest during erythropoiesis with a reduced reticulocyte production in contrast with erythroid hyperplasia in bone marrow. The latter shows specific morphological abnormalities that allowed for a morphological classification of these conditions mainly represented by congenital dyserythropoietic anemias types I and II. The identification of their causative genes provided evidence that these conditions have different molecular mechanisms that induce abnormal cell maturation and division. Some altered proteins seem to be involved in the chromatin assembly, such as codanin-1 in congenital dyserythropoietic anemia I. The gene involved in congenital dyserythropoietic anemia II, the most frequent form, is SEC23B. This condition seems to belong to a group of diseases attributable to defects in the transport of newly synthesized proteins from endoplasmic reticulum to the Golgi. This review will analyze recent insights in congenital dyserythropoietic anemias types I and II. It will also attempt to clarify the relationship between mutations in causative genes and the clinical phenotype of these conditions. Key words: dyserythropoiesis, congenital dyserythropoietic anemia, red blood cells, inherited anemias.Citation: Iolascon A, Esposito MR, and Russo R. Clinical aspects and pathogenesis of congenital dyserythropoietic anemias: from morphology to molecular approach. Haematologica 2012;97(12): 1786-1794. doi:10.3324/haematol.2012 This is an open-access paper. ABSTRACT © F e r r a t a S t o r t i F o u n d a t i o nto distinguish without molecular evaluation. 7,8 Recent identification of several causative genes could help reclassify these disorders (Table 1). Variant forms are very rare and this, up to now, has compromised further molecular studies. Linkage studies had previously been the main tool to clarify the genetics of Mendelian disorders; however, extremely rare disorders or sporadic cases caused by de novo variants are not appropriate for this type of study design. Exome sequencing is now becoming technically feasible and more cost-effective due to the recent advances in high-throughput sequence capture methods and next-generation sequencing technologies that have offered new opportunities for research into Mendelian disorders. 9 We suggest that the use of these new technologies will lead to the identification of new causative genes in CDA variants in the near future. In particular, this review will deal with new insights on the two most frequent forms of CDAs: types I and II. Epidemiology of CDAsUntil December 2011, 712 cases from 614 families were included in the German CDA Registry, 10,11 whereas 206Clinical aspects and pathogenesis of CDAs haematologica | 2012; 97 (12) 1787 © F e r r a t a S t o r t i F o u n d a t i o ncases from 183 families were enrolled in the Italian CDA registry (A Iolascon, unpublished data, 2011 Although CDA II patients are to be found right across the Italian peninsula, the maj...

Neomorphic effects of the neonatal anemia (Nan-Eklf) mutation contribute to deficits throughout development

“…In the present case, the most direct connection is with CDA type IV (Iolascon et al, 2012), which is caused by a mutation in human KLF1 at the same amino acid (Arnaud et al, 2010;Jaffray et al, 2013;Singleton et al, 2011). The change is non-conservative (E to K), so although not all characteristics of the Nan mouse may apply, individuals with CDA exhibit altered globin switching and membrane deficits that are highly reminiscent of the present model (discussed by Siatecka et al, 2010b).…”

Compound heterozygosity for KLF1 mutations is associated with microcytic hypochromic anemia and increased fetal hemoglobin

“…Originally, three major types (CDA I, II, and III) were recognized based on characteristic morphological aberrations. 5,6 The first of these to be described genetically was CDA I, 7 for which 60% of patients have bone marrow abnormalities resulting from mutations in the codanin-1 gene (CDAN1). 6 C15ORF41 was later identified as another cause of CDA I in pedigrees that were negative for CDAN1 mutations.…”

“…5,6 The first of these to be described genetically was CDA I, 7 for which 60% of patients have bone marrow abnormalities resulting from mutations in the codanin-1 gene (CDAN1). 6 C15ORF41 was later identified as another cause of CDA I in pedigrees that were negative for CDAN1 mutations. 8 Recent studies have attributed CDAII and CDAIII to mutations in SEC23B and KIF23, respectively.…”

Characteristic phenotypes associated with congenital dyserythropoietic anemia (type II) manifest at different stages of erythropoiesis

“…Clinically, patients present with typical symptoms associated with hemolytic anemia of variable degree, erythroid hyperplasia, splenomegaly, gallstones and iron overload. [1][2][3] Other characteristic features of CDAII include erythrocytes with hypoglycosylated membrane proteins including band 3, and the glucose transporter Glut1 [4][5][6][7] and a "double plasma membrane" due to residual endoplasmic reticulum, that stains positively for endoplasmic reticulum (ER) protein markers GRP78, calreticulin and protein disulfide isomerase (PDI). 8 The stage at which the characteristic features of CDAII observed in patients' erythrocytes manifest during erythropoiesis is currently unknown.…”