RESUMO
Lipin2 is a phosphatidate phosphatase that plays critical roles in fat homeostasis. Alterations in Lpin2, which encodes lipin2, cause the autoinflammatory bone disorder Majeed syndrome. Lipin2 limits lipopolysaccharide (LPS)-induced inflammatory responses in macrophages. However, little is known about the precise molecular mechanisms underlying its anti-inflammatory function. In this study, we attempted to elucidate the molecular link between the loss of lipin2 function and autoinflammatory bone disorder. Using a Lpin2 knockout murine macrophage cell line, we showed that lipin2 deficiency enhances innate immune responses to LPS stimulation through excessive activation of the NF-κB signaling pathway, partly because of TAK1 signaling upregulation. Lipin2 depletion also enhanced RANKL-mediated osteoclastogenesis and osteoclastic resorption activity accompanied by NFATc1 dephosphorylation and increased nuclear accumulation. These results suggest that lipin2 suppresses the development of autoinflammatory bone disorder by fine-tuning proinflammatory responses and osteoclastogenesis in macrophages. Therefore, this study provides insights into the molecular pathogenesis of monogenic autoinflammatory bone disorders and presents a potential therapeutic intervention.
Assuntos
Anemia Diseritropoética Congênita/genética , Síndromes de Imunodeficiência/genética , Inflamação/genética , MAP Quinase Quinase Quinases/genética , Fatores de Transcrição NFATC/genética , Proteínas Nucleares/genética , Osteomielite/genética , Tecido Adiposo/metabolismo , Tecido Adiposo/patologia , Anemia Diseritropoética Congênita/metabolismo , Anemia Diseritropoética Congênita/patologia , Animais , Reabsorção Óssea/genética , Reabsorção Óssea/metabolismo , Reabsorção Óssea/patologia , Diferenciação Celular/genética , Humanos , Síndromes de Imunodeficiência/metabolismo , Síndromes de Imunodeficiência/patologia , Inflamação/metabolismo , Inflamação/patologia , Lipopolissacarídeos/genética , Macrófagos/metabolismo , Macrófagos/patologia , Camundongos , Camundongos Knockout , NF-kappa B/genética , Proteínas Nucleares/deficiência , Proteínas Nucleares/metabolismo , Osteoclastos/metabolismo , Osteogênese/genética , Osteomielite/metabolismo , Osteomielite/patologia , Ligante RANK/genética , Transdução de Sinais/genética , Fator de Transcrição RelA/genéticaRESUMO
The Congenital Dyserythropoietic Anemia (CDA) Registry was established with the goal to facilitate investigations of natural history, biology, and molecular pathogenetic mechanisms of CDA. Three unrelated individuals enrolled in the registry had a syndrome characterized by CDA and severe neurodevelopmental delay. They were found to have missense mutations in VPS4A, a gene coding for an ATPase that regulates the ESCRT-III machinery in a variety of cellular processes including cell division, endosomal vesicle trafficking, and viral budding. Bone marrow studies showed binucleated erythroblasts and erythroblasts with cytoplasmic bridges indicating abnormal cytokinesis and abscission. Circulating red blood cells were found to retain transferrin receptor (CD71) in their membrane, demonstrating that VPS4A is critical for normal reticulocyte maturation. Using proband-derived induced pluripotent stem cells (iPSCs), we have successfully modeled the hematologic aspects of this syndrome in vitro, recapitulating their dyserythropoietic phenotype. Our findings demonstrate that VPS4A mutations cause cytokinesis and trafficking defects leading to a human disease with detrimental effects to erythropoiesis and neurodevelopment.
Assuntos
ATPases Associadas a Diversas Atividades Celulares/genética , Anemia Diseritropoética Congênita/genética , Complexos Endossomais de Distribuição Requeridos para Transporte/genética , ATPases Vacuolares Próton-Translocadoras/genética , Adenosina Trifosfatases/metabolismo , Anemia Diseritropoética Congênita/patologia , Medula Óssea/patologia , Células da Medula Óssea/metabolismo , Criança , Pré-Escolar , Citocinese , Endossomos/metabolismo , Eritroblastos/metabolismo , Eritrócitos/citologia , Eritropoese , Feminino , Humanos , Células-Tronco Pluripotentes Induzidas/citologia , Masculino , Transtornos do Neurodesenvolvimento/metabolismo , Fenótipo , Transporte Proteico , Reticulócitos/citologiaRESUMO
Congenital dyserythropoietic anemia type II (CDA II) is a hypo-productive anemia defined by ineffective erythropoiesis through maturation arrest of erythroid precursors. CDA II is an autosomal recessive disorder due to loss-of-function mutations in SEC23B. Currently, management of patients with CDA II is based on transfusions, splenectomy, or hematopoietic stem-cell transplantation. Several studies have highlighted benefits of ACE-011 (sotatercept) treatment of ineffective erythropoiesis, which acts as a ligand trap against growth differentiation factor (GDF)11. Herein, we show that GDF11 levels are increased in CDA II, which suggests sotatercept as a targeted therapy for treatment of these patients. Treatment of stable clones of SEC23B-silenced erythroleukemia K562 cells with the iron-containing porphyrin hemin plus GDF11 increased expression of pSMAD2 and reduced nuclear localization of the transcription factor GATA1, with subsequent reduced gene expression of erythroid differentiation markers. We demonstrate that treatment of these SEC23B-silenced K562 cells with RAP-011, a "murinized" ortholog of sotatercept, rescues the disease phenotype by restoring gene expression of erythroid markers through inhibition of the phosphorylated SMAD2 pathway. Our data also demonstrate the effect of RAP-011 treatment in reducing the expression of erythroferrone in vitro, thus suggesting a possible beneficial role of the use of sotatercept in the management of iron overload in patients with CDA II.
Assuntos
Anemia Diseritropoética Congênita/tratamento farmacológico , Proteínas Morfogenéticas Ósseas/genética , Fator de Transcrição GATA1/genética , Fatores de Diferenciação de Crescimento/genética , Proteínas Recombinantes de Fusão/farmacologia , Proteínas de Transporte Vesicular/genética , Anemia Diseritropoética Congênita/genética , Anemia Diseritropoética Congênita/patologia , Células Precursoras Eritroides/metabolismo , Eritropoese/genética , Feminino , Humanos , Células K562 , Mutação/genética , Fenótipo , Proteínas Recombinantes de Fusão/genética , Proteína Smad2/genética , Proteína Smad3/genéticaRESUMO
Congenital dyserythropoietic anemias comprise a group of very rare hereditary disorders characterized by ineffective erythropoiesis and distinct morphologic abnormalities of the erythroblasts in the bone marrow. The wide variety of phenotypes observed in these patients makes the diagnosis difficult; identification of the genetic variants is crucial in differential diagnosis and clinical management. We report the nineth case with congenital dyserythropoietic anemia type IV, with a novel mutation that has not been reported before.
Assuntos
Anemia Diseritropoética Congênita/patologia , Fatores de Transcrição Kruppel-Like/genética , Mutação , Anemia Diseritropoética Congênita/genética , Humanos , Lactente , Masculino , Fenótipo , PrognósticoAssuntos
Anemia Diseritropoética Congênita/genética , Osso e Ossos/anormalidades , Unhas Malformadas/congênito , Anemia Diseritropoética Congênita/classificação , Anemia Diseritropoética Congênita/diagnóstico , Anemia Diseritropoética Congênita/patologia , Células da Medula Óssea/patologia , Osso e Ossos/patologia , Eritroblastos/patologia , Dedos/anormalidades , Dedos/patologia , Glicoproteínas/genética , Humanos , Lactente , Fatores de Transcrição Kruppel-Like/genética , Masculino , Proteínas Associadas aos Microtúbulos/genética , Mutação , Unhas/patologia , Unhas Malformadas/patologia , Proteínas Nucleares/genética , Sindactilia/genética , Proteínas de Transporte Vesicular/genéticaRESUMO
Currently, there is no guideline for the treatment of patients with congenital dyserythropoietic anemia (CDA) type II. One approach is to follow-up patients with transfusions, on the basis of individually determined target hemoglobin levels, and iron chelation according to the thalassemia guidelines. In some transfusion-dependent CDA II patients, splenectomy reduces the number of transfusions; however, the only known curative option for CDA II patients is hematopoietic stem cell transplantation (HSCT). Only a few published case reports of allogeneic HSCT in CDA II patients are available. Here, we review the literature and add our data of a CDA II patient who developed transfusion dependence and was cured with HSCT.
Assuntos
Anemia Diseritropoética Congênita/terapia , Transplante de Células-Tronco Hematopoéticas/métodos , Anemia Diseritropoética Congênita/patologia , Pré-Escolar , Feminino , Humanos , Lactente , PrognósticoRESUMO
Krüppel-like factor 1 (KLF1), a transcription factor controlling definitive erythropoiesis, is involved in sequential control of terminal cell division and enucleation via fine regulation of key cell cycle regulator gene expression in erythroid lineage cells. Type IV congenital dyserythropoietic anemia (CDA) is caused by a monoallelic mutation at the second zinc finger of KLF1 (c.973G>A, p.E325K). We recently diagnosed a female patient with type IV CDA with the identical missense mutation. To understand the mechanism underlying the dyserythropoiesis caused by the mutation, we generated induced pluripotent stem cells (iPSCs) from the CDA patient (CDA-iPSCs). The erythroid cells that differentiated from CDA-iPSCs (CDA-erythroid cells) displayed multinucleated morphology, absence of CD44, and dysregulation of the KLF1 target gene expression. In addition, uptake of bromodeoxyuridine by CDA-erythroid cells was significantly decreased at the CD235a+/CD71+ stage, and microarray analysis revealed that cell cycle regulator genes were dysregulated, with increased expression of negative regulators such as CDKN2C and CDKN2A. Furthermore, inducible expression of the KLF1 E325K, but not the wild-type KLF1, caused a cell cycle arrest at the G1 phase in CDA-erythroid cells. Microarray analysis of CDA-erythroid cells and real-time polymerase chain reaction analysis of the KLF1 E325K inducible expression system also revealed altered expression of several KLF1 target genes including erythrocyte membrane protein band 4.1 (EPB41), EPB42, glutathione disulfide reductase (GSR), glucose phosphate isomerase (GPI), and ATPase phospholipid transporting 8A1 (ATP8A1). Our data indicate that the E325K mutation in KLF1 is associated with disruption of transcriptional control of cell cycle regulators in association with erythroid membrane or enzyme abnormalities, leading to dyserythropoiesis.
Assuntos
Anemia Diseritropoética Congênita , Diferenciação Celular/genética , Células Eritroides , Pontos de Checagem da Fase G1 do Ciclo Celular/genética , Células-Tronco Pluripotentes Induzidas , Fatores de Transcrição Kruppel-Like , Mutação de Sentido Incorreto , Adulto , Substituição de Aminoácidos , Anemia Diseritropoética Congênita/genética , Anemia Diseritropoética Congênita/metabolismo , Anemia Diseritropoética Congênita/patologia , Inibidor p16 de Quinase Dependente de Ciclina/genética , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Inibidor de Quinase Dependente de Ciclina p18/genética , Inibidor de Quinase Dependente de Ciclina p18/metabolismo , Células Eritroides/metabolismo , Células Eritroides/patologia , Feminino , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Células-Tronco Pluripotentes Induzidas/patologia , Fatores de Transcrição Kruppel-Like/genética , Fatores de Transcrição Kruppel-Like/metabolismoRESUMO
We report a rare case of severe congenital dyserythropoietic anemia type 1 with fetal onset. Our patient presented with fetal hydrops from 19 weeks of gestation, requiring multiple intrauterine transfusions. At birth, she had severe hemolytic anemia with severe jaundice, and was subsequently transfusion dependent. She eventually developed severe iron overload and fulminant liver failure before her demise at 5 months of age. Genetic testing revealed a novel mutation in CDAN1.
Assuntos
Anemia Diseritropoética Congênita , Colestase Intra-Hepática , Glicoproteínas/genética , Hidropisia Fetal , Sobrecarga de Ferro , Mutação , Índice de Gravidade de Doença , Anemia Diseritropoética Congênita/genética , Anemia Diseritropoética Congênita/patologia , Colestase Intra-Hepática/genética , Colestase Intra-Hepática/patologia , Feminino , Humanos , Hidropisia Fetal/genética , Hidropisia Fetal/patologia , Lactente , Sobrecarga de Ferro/genética , Sobrecarga de Ferro/patologia , Proteínas NuclearesAssuntos
Anemia Diseritropoética Congênita/patologia , Núcleo Celular/patologia , Síndromes Mielodisplásicas/patologia , Anemia Diseritropoética Congênita/diagnóstico , Biomarcadores , Medula Óssea/patologia , Células da Medula Óssea/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/diagnósticoRESUMO
We identified a child with KLF1-E325K congenital dyserythropoietic anemia type IV who experienced a severe clinical course, fetal anemia, hydrops fetalis, and postnatal transfusion dependence only partially responsive to splenectomy. The child also had complete sex reversal, the cause which remains undetermined. To gain insights into our patient's severe hematologic phenotype, detailed analyses were performed. Erythrocytes from the patient and parents demonstrated functional abnormalities of the erythrocyte membrane, attributed to variants in the α-spectrin gene. Hypomorphic alleles in SEC23B and YARS2 were also identified. We hypothesize that coinheritance of variants in relevant erythrocyte genes contribute to the clinical course in our patient and other E325K-linked congenital dyserythropoietic anemia IV patients with severe clinical phenotypes.
Assuntos
Anemia Diseritropoética Congênita/genética , Transtornos do Desenvolvimento Sexual/genética , Hidropisia Fetal/genética , Fatores de Transcrição Kruppel-Like/genética , Mutação de Sentido Incorreto , Substituição de Aminoácidos , Anemia Diseritropoética Congênita/patologia , Anemia Diseritropoética Congênita/terapia , Transtornos do Desenvolvimento Sexual/patologia , Transtornos do Desenvolvimento Sexual/terapia , Humanos , Hidropisia Fetal/patologia , Hidropisia Fetal/terapia , Recém-Nascido , Masculino , Índice de Gravidade de Doença , Proteínas de Transporte Vesicular/genéticaRESUMO
Congenital dyserythropoietic anemias (CDAs) are inherited disorders hallmarked by chronic hyporegenerative anemia, relative reticulocytopenia, hemolytic component and iron overload. They represent a subtype of the inherited bone marrow failure syndromes, characterized by impaired differentiation and proliferation of the erythroid lineage. Three classical types were defined by marrow morphology, even if the most recent classification recognized six different genetic types. The pathomechanisms of CDAs are different, but all seem to involve the regulation of DNA replication and cell division. CDAs are often misdiagnosed, since either morphological abnormalities or clinical features can be commonly identified in other clinically-related anemias. However, differential diagnosis is essential for guiding both follow up and management of the patients.
Assuntos
Anemia Diseritropoética Congênita/diagnóstico , Anemia Diseritropoética Congênita/terapia , Anemia Diseritropoética Congênita/complicações , Anemia Diseritropoética Congênita/patologia , Animais , Medula Óssea/patologia , Diagnóstico Diferencial , Gerenciamento Clínico , Humanos , Sobrecarga de Ferro/complicaçõesAssuntos
Anemia Diseritropoética Congênita/genética , Mutação de Sentido Incorreto , Mutação Puntual , Proteínas de Transporte Vesicular/genética , Adolescente , Anemia Diseritropoética Congênita/diagnóstico , Anemia Diseritropoética Congênita/patologia , Medula Óssea/patologia , Núcleo Celular/ultraestrutura , Diagnóstico Tardio , Células Precursoras Eritroides/ultraestrutura , Éxons/genética , Feminino , Hepatomegalia/etiologia , Heterozigoto , Humanos , Icterícia/etiologia , Esplenomegalia/etiologiaRESUMO
Congenital dyserythropoietic anemia type II (CDAII) is an autosomal recessive disease of ineffective erythropoiesis characterized by increased bi/multinucleated erythroid precursors in the bone marrow. CDAII results from mutations in SEC23B. The SEC23 protein is a core component of coat protein complex II-coated vesicles, which transport secretory proteins from the endoplasmic reticulum to the Golgi apparatus. Though the genetic defect underlying CDAII has been identified, the pathophysiology of this disease remains unknown. We previously reported that SEC23B-deficient mice die perinatally, exhibiting massive pancreatic degeneration, with this early mortality limiting evaluation of the adult hematopoietic compartment. We now report that mice with SEC23B deficiency restricted to the hematopoietic compartment survive normally and do not exhibit anemia or other CDAII characteristics. We also demonstrate that SEC23B-deficient hematopoietic stem cells (HSC) do not exhibit a disadvantage at reconstituting hematopoiesis when compared directly to wild-type HSC in a competitive repopulation assay. Secondary bone marrow transplants demonstrated continued equivalence of SEC23B-deficient and WT HSC in their hematopoietic reconstitution potential. The surprising discordance in phenotypes between SEC23B-deficient mice and humans may reflect an evolutionary shift in SEC23 paralog function and/or expression, or a change in a specific COPII cargo critical for erythropoiesis.
Assuntos
Anemia Diseritropoética Congênita/fisiopatologia , Eritrócitos/patologia , Proteínas de Transporte Vesicular/sangue , Proteínas de Transporte Vesicular/genética , Anemia Diseritropoética Congênita/genética , Anemia Diseritropoética Congênita/patologia , Animais , Modelos Animais de Doenças , Eritropoese/genética , Regulação da Expressão Gênica , Transplante de Células-Tronco Hematopoéticas , Células-Tronco Hematopoéticas/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Fenótipo , Proteínas de Transporte Vesicular/metabolismoRESUMO
Pyruvate kinase (PK) deficiency is the commonest enzyme deficiency in the glycolytic pathway leading to hemolytic anemia secondary to decreased Adenosine Triphosphate (ATP) synthesis in the red cells. synthesis. PK deficiency due to mutations in the PKLR (1q21) gene leads to highly variable clinical presentation ranging from severe fetal anemia to well compensated anemia in adults. We describe dyserythropoiesis in the bone marrow of a child with transfusion dependent anemia and unilateral multicystic dysplastic kidney (MCDK) mimicking Congenital Dyserythropoietic Anemia type I (CDA type I). Persistently low erythrocyte PK levels and double heterozygous mutations present in the PKLR gene confirmed the diagnosis of PK deficiency.
Assuntos
Anemia Diseritropoética Congênita , Anemia Hemolítica Congênita não Esferocítica , Rim Displásico Multicístico , Mutação , Piruvato Quinase/deficiência , Erros Inatos do Metabolismo dos Piruvatos , Adulto , Anemia Diseritropoética Congênita/complicações , Anemia Diseritropoética Congênita/genética , Anemia Diseritropoética Congênita/patologia , Anemia Hemolítica Congênita não Esferocítica/complicações , Anemia Hemolítica Congênita não Esferocítica/genética , Anemia Hemolítica Congênita não Esferocítica/patologia , Feminino , Humanos , Recém-Nascido , Masculino , Rim Displásico Multicístico/complicações , Rim Displásico Multicístico/genética , Rim Displásico Multicístico/patologia , Piruvato Quinase/genética , Erros Inatos do Metabolismo dos Piruvatos/complicações , Erros Inatos do Metabolismo dos Piruvatos/genética , Erros Inatos do Metabolismo dos Piruvatos/patologiaRESUMO
Congenital dyserythropoietic anemia (CDA) type-1 is a rare genetic disorder of ineffective erythropoiesis, which manifests in macrocytic anemia. We report a CDA1 patient who as a newborn presented with macrocytic anemia and persistent pulmonary hypertension of the newborn (PPHN) requiring mechanical ventilation. Post-infancy, the patient developed acral dysmorphism and pectus excavatum the latter rarely found in CDA1. Patient is a compound heterozygote for a known maternal-derived missense-mutation (c.1796A > G/p.Asn589Ser) and a novel paternal-derived deletion-mutation (c.1104_1106del/Phe365del) in CDAN1. This report highlights the importance of recognizing PPHN as a presenting symptom of CDA1 and expands the repertoire of the accompanying mutations and axial skeletal malformations.
Assuntos
Anemia Diseritropoética Congênita , Glicoproteínas/genética , Hipertensão Pulmonar , Mutação de Sentido Incorreto , Tórax/anormalidades , Substituição de Aminoácidos , Anemia Diseritropoética Congênita/complicações , Anemia Diseritropoética Congênita/genética , Anemia Diseritropoética Congênita/patologia , Humanos , Hipertensão Pulmonar/complicações , Hipertensão Pulmonar/genética , Hipertensão Pulmonar/patologia , Recém-Nascido , Masculino , Proteínas NuclearesRESUMO
Haplotype analysis and targeted next-generation resequencing allowed us to identify a mutation in the KIF23 gene and to show its association with an autosomal dominant form of congenital dyserythropoietic anemia type III (CDA III). The region at 15q23 where CDA III was mapped in a large Swedish family was targeted by array-based sequence capture in a female diagnosed with CDA III and her healthy sister. Prioritization of all detected sequence changes revealed 10 variants unique for the CDA III patient. Among those variants, a novel mutation c.2747C>G (p.P916R) was found in KIF23, which encodes mitotic kinesin-like protein 1 (MKLP1). This variant segregates with CDA III in the Swedish and American families but was not found in 356 control individuals. RNA expression of the 2 known splice isoforms of KIF23 as well as a novel one lacking the exons 17 and 18 was detected in a broad range of human tissues. RNA interference-based knock-down and rescue experiments demonstrated that the p.P916R mutation causes cytokinesis failure in HeLa cells, consistent with appearance of large multinucleated erythroblasts in CDA III patients. We conclude that CDA III is caused by a mutation in KIF23/MKLP1, a conserved mitotic kinesin crucial for cytokinesis.
Assuntos
Processamento Alternativo , Anemia Diseritropoética Congênita/etiologia , Biomarcadores Tumorais/genética , Proteínas Associadas aos Microtúbulos/genética , Mutação/genética , Sequência de Aminoácidos , Anemia Diseritropoética Congênita/patologia , Segregação de Cromossomos , Citocinese , Feminino , Células HeLa , Humanos , Masculino , Dados de Sequência Molecular , Linhagem , Reação em Cadeia da Polimerase , Prognóstico , Homologia de Sequência de AminoácidosRESUMO
Erythrocytes contain oxygen-carrying hemoglobin to all body cells. Impairments in the generation of erythrocytes, a process known as erythropoiesis, or in hemoglobin synthesis alter cell function because of decreased oxygen supply and lead to anemic diseases. Thus, understanding how erythropoiesis is regulated during embryogenesis and adulthood is important to develop novel therapies for anemia. The zebrafish, Danio rerio, provides a powerful model for such study. Their small size and the ability to generate a large number of embryos enable large-scale analysis, and their transparency facilitates the visualization of erythroid cell migration. Importantly, the high conservation of hematopoietic genes among vertebrates and the ability to successfully transplant hematopoietic cells into fish have enabled the establishment of models of human anemic diseases in fish. In this review, we summarize the current progress in our understanding of erythropoiesis on the basis of zebrafish studies and highlight fish models of human anemias. These analyses could enable the discovery of novel drugs as future therapies.
Assuntos
Anemia/patologia , Eritropoese/fisiologia , Anemia/metabolismo , Anemia Diseritropoética Congênita/metabolismo , Anemia Diseritropoética Congênita/patologia , Anemia Hipocrômica/metabolismo , Anemia Hipocrômica/patologia , Anemia Sideroblástica/metabolismo , Anemia Sideroblástica/patologia , Animais , Anquirinas/deficiência , Anquirinas/metabolismo , Proteínas de Transporte de Cátions/deficiência , Proteínas de Transporte de Cátions/metabolismo , Modelos Animais de Doenças , Eritrócitos/citologia , Doenças Genéticas Ligadas ao Cromossomo X/metabolismo , Doenças Genéticas Ligadas ao Cromossomo X/patologia , Hemocromatose/metabolismo , Hemocromatose/patologia , Esferocitose Hereditária/metabolismo , Esferocitose Hereditária/patologia , Peixe-ZebraAssuntos
Anemia Diseritropoética Congênita , Eritroblastos/metabolismo , Eritroblastos/ultraestrutura , Adulto , Anemia Diseritropoética Congênita/sangue , Anemia Diseritropoética Congênita/classificação , Anemia Diseritropoética Congênita/patologia , Medula Óssea/metabolismo , Medula Óssea/ultraestrutura , Humanos , MasculinoRESUMO
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 genome-wide epigenetic landscape of several histone modifications is maintained. However, immunofluorescence analysis of intermediate erythroblasts from patients with CDA-1 reveals abnormal accumulation of HP1α in the Golgi apparatus. A link between mutant codanin-1 and the aberrant localization of HP1α is supported by the finding that codanin-1 can be coimmunoprecipitated by anti-HP1α 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.