Codanin-1 mutations in congenital dyserythropoietic anemia type 1 affect HP1α localization in erythroblasts

Abstract

Congenital dyserythropoietic anemia type 1 (CDA-1), a rare inborn anemia characterized by abnormal chromatin ultrastructure in erythroblasts, is caused by abnormalities in codanin-1, a highly conserved protein of unknown function. We have produced 3 monoclonal antibodies to codanin-1 that demonstrate its distribution in both nucleus and cytoplasm by immunofluorescence and allow quantitative measurements of patient and normal material by Western blot. A detailed analysis of chromatin structure in CDA-1 erythroblasts shows no abnormalities in overall histone composition, and the genomewide epigenetic landscape of several histone modifications is maintained. However, immunofluorescence analysis of intermediate erythroblasts from patients with CDA-1 reveals abnormal accumulation of HP1␣ in the Golgi apparatus. A link between mutant codanin-1 and the aberrant localization of HP1␣ is supported by the finding that codanin-1 can be coimmunoprecipitated by anti-HP1␣ antibodies. Furthermore, we show colocalization of codanin-1 with Sec23B, the protein defective in CDA-2 suggesting that the CDAs might be linked at the molecular level. Mice containing a gene-trapped Cdan1 locus demonstrate its widespread expression during development. Cdan1 gt/gt homozygotes die in utero before the onset of primitive erythropoiesis, suggesting that Cdan1 has other critical roles during embryogenesis. (Blood. 2011;117(25): 6928-6938) IntroductionThe congenital dyserythropoietic anemias (CDAs) are a heterogeneous group of rare inborn disorders mainly affecting erythropoiesis. 1 Distinct from other inherited bone marrow failure syndromes, they are marked by morphologic abnormalities of the erythroblasts that lead to ineffective erythropoiesis/dyserythropoiesis, whereas the other hematopoietic lineages appear to be unaffected. Based largely on the dysplastic changes observed in erythroblasts by light and electron microscopy, the CDAs have been divided into 3 major types, designated CDA types 1, 2, and 3 2 ; causative genes have been identified for CDA-1 (CDAN1/codanin-1) 3 and CDA-2 (CDAN2/Sec23B), 4 whereas only the chromosomal locus is known for . 5 In CDA-1, the majority of cases come to attention during childhood and adolescence, often within episodes of erythropoietic stress (ie, infection, and in young women, pregnancy). 6,7 Severe presentations can include gallstones, chronic hyperbilirubinemia, and/or extramedullary hematopoietic foci in the parietal and frontal bones of the skull (as observed in thalassemia). Although iron overloading is rarely the revelatory sign, it seems to be present in the majority of patients after childhood. In some cases, skeletal or other dysmorphic features can be identified, including short stature, distal limb and nail malformations, vertebral deformations/dysplasias, and skin pigmentation defects. 1 The anemia is macrocytic with mean corpuscular volumes up to 120 fL, and the blood smear shows anisopoikilocytosis, basophilic stippling, and an inadequate reticulocyte response compared with hemolytic anemias....

The COPII pathway and hematologic disease

“…Multiple congenital dyserythropoietic disorders (reviewed in Iolascon et al 96 ) share common features with CDAII. CDAI was recently shown to be due to mutations in the gene encoding CODANIN-1, a protein known to colocalize with SEC23B, 97 suggesting a common pathophysiologic mechanism. However, a similar molecular link to other related dyserythropoietic disorders has not yet been identified.…”

The genetic basis of parental care evolution in monogamous mice

“…Of the 498 genes encompassed by both the male and female QTL regions, 34 had interspecific differences (Supplementary Data File 1), but only four were predicted to affect protein function (absolute PROVEAN 17 score > 2.5): sulfide quinone reductase-like and mitochondrial antiviral signaling protein, which localize to mitochondria 18,19 , congenital dyserythropoietic anemia type I, which is expressed ubiquitously and involved in erythropoiesis 20 , and glial cell line derived neurotrophic factor family receptor alpha 4, a protein not expressed in the brain 21 . None were strong candidates to affect nest building.…”

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.…”