Congenital dyserythropoietic anemia type I (CDA-I) is a rare hereditary disease marked by ineffective erythropoiesis, a characteristic spongy heterochromatin structure in erythroblasts, and mutations in the genes CDAN1 and CDIN1, which encode the proteins Codanin1 and CDIN1. Codanin1 regulates histone shuttling via the chaperone ASF1, yet the role of CDIN1 in CDA-I pathology remains unclear. Notably, CDIN1 is known to interact directly with the C-terminus of Codanin1. Although mutations in both genes are critical to the disease phenotype, their molecular-level effects have not been fully elucidated. Here, we present a comprehensive structural and functional analysis of the CDIN1-Codanin1 C-terminus complex. Using complementary biophysical techniques, we show that CDIN1 and Codanin1 C-terminus form a high-affinity heterodimeric complex with equimolar stoichiometry. We further delineate the essential interacting regions of CDIN1 and Codanin1. We demonstrate that CDA-I-associated mutations in either protein disrupt the CDIN1-Codanin1 interaction, suggesting a potential molecular mechanism underlying the disease.

Codanin-1 (CDAN1) is an essential and ubiquitous protein named after congenital dyserythropoietic anemia type I, an autosomal recessive disease that manifests from mutations in CDAN1 or CDIN1 (CDAN1 interacting nuclease 1). CDAN1 interacts with CDIN1 and the paralogous histone H3-H4 chaperones ASF1A (Anti-Silencing Function 1 A) and ASF1B. However, CDAN1 function remains unclear. Here, we analyze CDAN1 complexes using biochemistry, single-particle cryo-EM, and structural predictions. We find that CDAN1 dimerizes and assembles into cytosolic complexes with CDIN1 and multiple copies of ASF1A/B. One CDAN1 can engage two ASF1 through two B-domains commonly found in ASF1 binding partners and two helices that mimic histone H3 binding. We additionally show that ASF1A and ASF1B have different requirements for CDAN1 engagement. Our findings explain how CDAN1 sequesters ASF1A/B by occupying all functional binding sites known to facilitate histone chaperoning and provide molecular-level insights into this enigmatic complex.

Congenital dyserythropoietic anemia type I (CDA-I) is an autosomal recessive disorder marked by ineffective erythropoiesis, abnormal morphology of bone marrow erythroblasts, and iron overload. Most cases of CDA-I are caused by mutations in the CDAN1 gene, which encodes a ubiquitous protein of unknown function, Codanin-1. To investigate the role of Codanin-1 in the molecular pathways involved in CDA-I, we developed erythroid models using human K562 cells and primary human CD34 + cells from mobilized peripheral blood. Here we show that Codanin-1 expression is required for erythroid progenitor development and normal erythroid cell differentiation. Erythroid cells lacking Codanin-1 demonstrated morphologic changes similar to those observed in CDA-I. Global gene expression changes after Codanin-1 knockdown revealed alterations in a set of key erythroid genes. In particular, the AHSP gene, which showed reduced mRNA and protein expression levels after Codanin-1 knockdown, also demonstrated increased Codanin-1 occupancy at its gene regulatory region by chromatin immunoprecipitation coupled to high-throughput sequencing. In summary, using cell models recapitulating many features of CDA-I, we have studied and confirmed the importance of Codanin-1 during erythroid differentiation and provide mechanistic insight into how loss of Codanin-1 expression results in CDA-I.

Congenital dyserythropoietic anemia type I (CDA-I) is a rare disorder of erythropoiesis. All CDA-I patients are expected to have iron overload and chronic hemolysis. Patients with severe anemia may undergo splenectomy. Hemochromatosis, chronic hemolysis, and splenectomy are all found to increase risk for thromboembolism in thalassemic patients. As CDA-I patients have similar findings, we sought to evaluate prevalence of thromboembolic events (TEEs) in these patients. A retrospective case-control study was conducted, including 110 CDA-I patients (study group) and 326 age- and sex-matched iron deficiency anemia patients of the same ethnicity (control group). Patients were risk-stratified using Risk Assessment Models for thromboembolism. We identified 3 cases (2.7%) with TEEs in the CDA group and 1 case (0.3%) in the control group. All patients were females. VTE risk scores were low to moderate for CDA patients and higher for IDA patient. When compared to control group, CDA-I patients were nine times more likely to develop TEE (OR 9.11, 95% CI = 1.15-185.27, p = 0.057). All 3 CDA patients had a history of remarkable hemolysis and iron overload. Two underwent splenectomy. These findings show that CDA patients appear to be at increased risk for TEEs.

Congenital dyserythropoietic anemia type I (CDA-I) is a rare hereditary anemia caused by CDAN1 or C15orf41 mutations, with CDAN1-related cases responding to interferon-alpha (IFN-α) therapy. However, traditional IFN-α requires frequent injections and often causes flu-like symptoms, which can hinder long-term adherence. Here, we present the first documented use of ropeginterferon alfa-2b, a next-generation pegylated interferon, in two patients with CDA-I. Both patients, who were previously transfusion dependent, achieved transfusion independence and improved hemoglobin levels after transitioning from recombinant IFN-α to ropeginterferon alfa-2b with biweekly dosing. This treatment preserved efficacy while minimizing adverse effects and the injection burden. Our findings suggest that ropeginterferon alfa-2b may serve as a more tolerable and effective long-term treatment. Further prospective large-scale studies are needed to validate its broader clinical applicability.