Linkage and mutational analysis of the CDAN1 gene reveals genetic heterogeneity in congenital dyserythropoietic anemia type I

Ahmed, Momin; Chehal, Aref; Zahed, Laïla; Taher, Ali T.; Haidar, Joud H.; Shamseddine, Ali; O'Hea, Anne-Marie; Bienz, Nicola; Dgany, Orly; Avidan, Nili; Beckmann, Jacques S.; Tamary, Hannah; Higgs, Douglas R.; Vyas, Paresh; Wood, W. G.; Wickramasinghe, Sunitha N.

doi:10.1182/blood-2006-01-0081

Cited by 23 publications

(15 citation statements)

References 5 publications

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“…In two families (Kuwaiti and Pakistani), the disease gene did not show linkage to chromosome 15 markers around the CDAN1 locus, indicating that there is at least a second disease gene (Ahmed et al , 2003). Furthermore, in several sporadic cases only a single CDAN1 mutation was detected by exon sequencing and in one case, no CDAN1 mutations were found.…”

Section: Cda Type Imentioning

confidence: 93%

Advances in the understanding of the congenital dyserythropoietic anaemias

2005

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SummaryThe congenital dyserythropoietic anaemias (CDAs) are a heterogeneous group of diseases in which the anaemia is predominantly caused by dyserythropoiesis and marked ineffective erythropoiesis; three major (types I, II and III) and several minor subgroups have been identified. Additional information on the natural history of these conditions, the beneficial role of splenectomy in CDA type II and efficacy of interferon-a in type I have recently been reported. A disease gene has been localised to a chromosomal segment in the three major types and in CDA type I, a disease gene has been identified (CDANI). Mutations have been detected in both familial and sporadic cases but the predicted protein structure gives few clues as to its function. In both type I and II, there are cases unlinked to the identified localisations, suggesting genetic heterogeneity.

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Section: Cda Type Imentioning

confidence: 93%

Advances in the understanding of the congenital dyserythropoietic anaemias

2005

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“…The patients were Lebanese nonconsanguineous, homozygous carriers of the classic Bedouin mutation (3238C-T, R1040W) and have been described previously. 3,21 Erythroblasts were cultured from patients' mononuclear cells by the 2-phase method of Fibach et al 10 Under these conditions, the intermediate erythroblasts recapitulate the CDA-1 bone marrow findings. Their chromatin has the characteristic spongy ("Swiss cheese") appearance (Figure 2A) seen in this condition.…”

Section: Chromatin Structure In Primary Cda-1 Erythroblastsmentioning

confidence: 99%

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

Renella

Roberts

Brown

et al. 2011

Blood

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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....

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“…We found no likely pathogenic changes in the remaining 7 pedigrees suggesting the presence of at least a further causative locus. Clinical findings in Family 2 have been previously reported 8 as showing hematologic results typical of CDA-I (Online Supplementary Table S2) and a substantial proportion of the erythroblasts showing spongy heterochromatin upon EM (Figure 1). Blood indices of affected members of Family 3 indicate anemia (Online Supplementary Table S2) and EM of erythroblasts from individual II-2 shows the characteristic pattern of spongy heterochromatin ( Figure 1).…”

Section: Resultsmentioning

confidence: 94%