Codanin-1, the Product of the Gene Mutated In Congenital Dyserythropoietic Anemia Type I (CDA I), Binds to Histone Chaperone Asf1a and Inhibits Its Nucleosome Assembly Activity

Abstract Abstract 1004 Congenital dyserythropoietic anemia type I (CDA1) is an inherited recessive macrocytic anemia associated with ineffective erythropoiesis. The disorder is characterized by the accumulation of erythroid precursors containing spongy heterochromatin and internuclear chromatin bridges. The mutated gene (CDAN1) encodes an ubiquitously expressed protein (codanin-1) of unknown function. We have previously shown that codanin-1 is a direct transcriptional target of the E2F1 transcription factor and that the levels of codanin-1 increase during S-phase and decrease during mitosis. In an attempt to further define the role of codanin-1, we conducted a yeast two-hybrid screen using a human bone marrow library and found that codanin-1 binds to Asf1a. Asf1 (anti silencing function) is a H3/H4 histone chaperone involved in the chromatin structure dynamics by its role in nucleosome assembly and disassembly. Using coimmunoprecipitation experiments we confirmed that histone chaperone Asf1a is a direct binding partner of codanin-1. Minimal 100 amino acids domain of codanin-1, involved in binding Asf1, was identified and defined as the Asf1-binding domain. We found that codanin-1 binds to the conserved N-terminal core of Asf1a, where histones and other histone chaperones also bind. FLAG-tagged codanin-1 or its Asf1-binding domain immunoprecipitated from transfected Hela cells and subsequently coimmunoprecipitated histone H3 and Asf1a simultaneously. A pull-down assay of purified Asf1-binding domain in the presence of core histones showed, however, no direct binding of this domain of codanin-1 to H3/H4 histones. By using the replication-independent nucleosome formation assay we noticed that the nucleosome assembly activity of GST-Asf1a was severely decreased by the addition of the purified Asf1-binding domain of codanin-1, a phenotype similar to the one observed in Asf1 depletion. One possible explanation is that binding of codanin-1 inhibits dissociation of histones from Asf1a, which therefore cannot be deposited onto DNA. It will be of interest to determine if codanin-1 is involved in modulating Asf1a activity in vivo and also in response to DNA replication or damage and to determine its role in erythroid heterochromatin formation. Disclosures: No relevant conflicts of interest to declare.

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Histone transfer among chaperones

Biochemical Society Transactions ◽

10.1042/bst20110737 ◽

2012 ◽

Vol 40 (2) ◽

pp. 357-363 ◽

Cited By ~ 17

Author(s):

Wallace H. Liu ◽

Mair E.A. Churchill

Keyword(s):

Histone H3 ◽

Histone Chaperone ◽

Chromatin Assembly ◽

Histone Chaperones ◽

Nucleosome Assembly ◽

Post Translational Modifications ◽

Chromatin Dynamics ◽

Nucleosomal Dna ◽

Chaperone Interactions ◽

Dependent Processes

The eukaryotic processes of nucleosome assembly and disassembly govern chromatin dynamics, in which histones exchange in a highly regulated manner to promote genome accessibility for all DNA-dependent processes. This regulation is partly carried out by histone chaperones, which serve multifaceted roles in co-ordinating the interactions of histone proteins with modification enzymes, nucleosome remodellers, other histone chaperones and nucleosomal DNA. The molecular details of the processes by which histone chaperones promote delivery of histones among their many functional partners are still largely undefined, but promise to offer insights into epigenome maintenance. In the present paper, we review recent findings on the histone chaperone interactions that guide the assembly of histones H3 and H4 into chromatin. This evidence supports the concepts of histone post-translational modifications and specific histone chaperone interactions as guiding principles for histone H3/H4 transactions during chromatin assembly.

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Disruption of NAP1 genes supresses the fas1 mutant phenotype and enhances genome stability

10.1101/2020.01.03.894170 ◽

2020 ◽

Author(s):

Karolína Kolářová ◽

Martina Nešpor Dadejová ◽

Tomáš Loja ◽

Eva Sýkorová ◽

Martina Dvořáčková

Keyword(s):

Genome Stability ◽

Genetic Interaction ◽

Plant Morphology ◽

Genotoxic Stress ◽

Histone Chaperone ◽

Micrococcal Nuclease ◽

Molecular Networks ◽

Histone Chaperones ◽

Loss Of Function ◽

Nucleosome Assembly

ABSTRACTHistone chaperones mediate assembly and disassembly of nucleosomes and participate in essentially all DNA-dependent cellular processes. In Arabidopsis thaliana, loss-of-functions of FAS1 or FAS2 subunits of the H3-H4 histone chaperone complex CHROMATIN ASSEMBLY FACTOR 1(CAF-1) has a dramatic effect on plant morphology, growth and overall fitness. Altered chromatin compaction, systematic loss of repetitive elements or increased DNA damage clearly demonstrate the severity of CAF-1 dysfunction. How histone chaperone molecular networks change without a functional CAF-1 remains elusive. Here we present an intriguing observation that disruption of the H2A-H2B histone chaperone NUCLEOSOME ASSEMBLY PROTEIN 1 (NAP1) supresses FAS1 loss-of function. The quadruple mutant fas1nap1;1-3 shows wild-type growth and decreased sensitivity to genotoxic stress. Chromatin of fas1nap1;1-3 plants is less accessible to micrococcal nuclease and progressive loss of telomeres and 45S rDNA is supressed. Interestingly, the strong genetic interaction between FAS1 and NAP1 does not occur via direct protein-protein interaction. We propose that NAP1;1-3 play an essential role in nucleosome assembly in fas1, thus their disruption abolishes fas1 defects. Our data altogether reveal a novel function of NAP1 proteins, unmasked by CAF-1 dysfunction. It emphasizes the importance of a balanced composition of chromatin and shed light on the histone chaperone molecular network.

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Congenital Dyserythropoietic Anemia Type I Due to Biallelic CDAN1 mutations: Report from the Congenital Dyserythropoietic Anemia Registry (CDAR)

Blood ◽

10.1182/blood-2019-128975 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3521-3521

Author(s):

Omar Niss ◽

Robert B. Lorsbach ◽

David K. Buchbinder ◽

Satheesh Chonat ◽

Morgan L. McLemore ◽

...

Keyword(s):

Bone Marrow ◽

Pulmonary Hypertension ◽

Neonatal Jaundice ◽

Macrocytic Anemia ◽

Advisory Board ◽

Type I ◽

Severe Anemia ◽

Congenital Dyserythropoietic Anemia ◽

Hematological Manifestations

Congenital dyserythropoietic anemias (CDA) are rare hereditary diseases of abnormal erythropoiesis. The CDA Registry of North America (CDAR) (NCT02964494) was opened in 2016 to investigate the natural history and molecular biology of CDA. CDA type I (CDA-I) is a recessive form of CDA characterized by macrocytic anemia, hemolysis with inadequate reticulocytosis, and iron overload. The bone marrow shows binucleated erythroblasts with chromatin bridges by light microscopy and spongy heterochromatin in erythroblasts by electron microscopy. The phenotypic heterogeneity in presentation and course of CDA-I is remarkable. Most CDA-I cases are caused by biallelic mutations in CDAN1or C15orf41, and 10-20% do not have an identifiable mutation. Non-hematological features, especially skeletal features, were historically reported in 10-20% of patients (Wickramasinghe, 1998). Due to the rarity of CDA-I and its clinical overlap with several disorders, the diagnosis is often missed or delayed by up to 17 yrs (median) (Roy, 2019). We describe in this study the characteristics and clinical course of CDA-I patients due to CDAN1 mutations enrolled in CDAR. Patients with a phenotypic diagnosis of CDA and their family members were enrolled in CDAR. Clinical and demographic data were gathered from participants at study entry and updated periodically thereafter. Participants elect to give blood, bone marrow, and DNA samples to the biorepository associated with CDAR. Participants with a phenotypic diagnosis of CDA-I and confirmed mutations in CDAN1 were included in this study. Six participants had a diagnosis of CDA-I due to biallelic CDAN1 mutations, comprising 18% (6/33) of affected CDAR participants. CDAN1 mutations were found in 75% of cases diagnosed phenotypically as CDA-I. All six participants presented early in life with a variable degree of non-immune hemolysis, and the diagnosis was confirmed within a median of 2 years from presentation. The characteristics of participants are summarized in table 1. Two had family history of stillbirth or fetal demise in older siblings due to hydrops fetalis. One participant presented prenatally with fetal anemia and started intrauterine transfusions at 24 weeks of gestation; 2 presented with severe anemia and signs of hydrops, pulmonary hypertension, transaminitis, severe hyperbilirubinemia, and thrombocytopenia at birth; and 3 presented with neonatal jaundice and moderate anemia. All participants required blood transfusions in the neonatal period. Three had spontaneous improvement and did not require transfusions after the first year of life. One remained transfusion-dependent at last follow up at the age of 4 yrs. One became transfusion-independent after starting interferon-alpha at 1 yr of age and did not need further transfusions even after discontinuation at 3 yrs of age. One had splenectomy at 11 y.o because he was misdiagnosed to have a membrane disorder but presented in adulthood with hemolytic anemia and pulmonary hypertension and was diagnosed at that time with CDA-I by genetic sequencing. All participants had one or more non-hematological manifestations, including hypertrophic skin folds, onychocryptosis, curved toenails, syndactyly, café-au-lait spots, macrocephaly, spinal fusion, scoliosis, and short stature. One participant suffered a thalamic stroke in the postnatal period, 2 had transient neonatal pulmonary hypertension in the setting of severe anemia, and one had pulmonary hypertension post-splenectomy in adulthood. Ferritin was high in all participants at last follow up, and 4 received chelation therapy. In summary, mutations in CDAN1 are the most common identified mutations in CDAR. CDA-I causes early-onset macrocytic anemia, which may present prenatally, with variable severity of hemolysis ranging from hydrops to mild neonatal jaundice and anemia. Non-hematological manifestations, mainly skeletal, nail and skin abnormalities are more common in CDA-I than previously reported, and their presence in infants with unexplained anemia should raise suspicion for the diagnosis. The availability of molecular testing has significantly accelerated the diagnosis. Management of patients with CDA-I requires multidisciplinary approach from an early age to improve outcome. Collaboration between clinicians, scientists, patients, and families is needed to advance the understanding and treatment of this rare disease. Disclosures Chonat: Alexion: Other: advisory board; Agios Pharmaceuticals, Inc.: Other: advisory board. Kalfa:Agios: Other: local PI of clinical research trial; FORMA: Other: sponsored research agreement.

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The histone chaperone FACT modulates nucleosome structure by tethering its components

Life Science Alliance ◽

10.26508/lsa.201800107 ◽

2018 ◽

Vol 1 (4) ◽

pp. e201800107 ◽

Cited By ~ 28

Author(s):

Tao Wang ◽

Yang Liu ◽

Garrett Edwards ◽

Daniel Krzizike ◽

Hataichanok Scherman ◽

...

Keyword(s):

Elongation Factor ◽

Histone Chaperone ◽

Nucleosome Assembly ◽

Transcription Elongation Factor ◽

Nucleosome Structure ◽

Mechanistic Insight ◽

Nucleosome Formation ◽

Nucleosome Disassembly ◽

Assembly Activity ◽

Insight Into

Human FAcilitates Chromatin Transcription (hFACT) is a conserved histone chaperone that was originally described as a transcription elongation factor with potential nucleosome assembly functions. Here, we show that FACT has moderate tetrasome assembly activity but facilitates H2A–H2B deposition to form hexasomes and nucleosomes. In the process, FACT tethers components of the nucleosome through interactions with H2A–H2B, resulting in a defined intermediate complex comprising FACT, a histone hexamer, and DNA. Free DNA extending from the tetrasome then competes FACT off H2A–H2B, thereby promoting hexasome and nucleosome formation. Our studies provide mechanistic insight into how FACT may stabilize partial nucleosome structures during transcription or nucleosome assembly, seemingly facilitating both nucleosome disassembly and nucleosome assembly.

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Autosomal Recessive Congenital Dyserythropoietic Anemia Type III Is Caused By Mutations in the Centralspindlin RACGAP1 Component

Blood ◽

10.1182/blood-2021-150097 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 847-847

Author(s):

Lídia Romero-Cortadellas ◽

Gonzalo Hernández ◽

Xènia Ferrer-Cortès ◽

Veronica Venturi ◽

Mireia Olivella ◽

...

Keyword(s):

Bone Marrow ◽

Missense Mutation ◽

Autosomal Recessive ◽

Conflicts Of Interest ◽

Case Reports ◽

Macrocytic Anemia ◽

Dominant Form ◽

Congenital Dyserythropoietic Anemia ◽

Type Iii ◽

Homozygous Missense Mutation

Abstract An autosomal dominant form of congenital dyserythropoietic anemia type III (CDA III) is caused by a missense mutation in the KIF23 gene whose protein product, mitotic kinesin-like protein (MKLP1), is part of the centralspindlin complex involved in cytokinesis. Several case reports suggested the existence of an autosomal recessive inheritance form of CDA III so far not genetically characterized. By means of whole exome sequencing in a Spanish CDA III family with healthy parents, we identified in the male proband a novel homozygous missense mutation p.Pro432Ser in the RACGAP1 gene, which encodes for the RACGAP1 protein (Rac GTPase-activating protein 1, also known as MgcRacGAP or CYK-4), the partner of MKLP1 in the centralspindlin complex. A second CDA III Spanish patient has a different rare and novel homozygous missense mutation, p.Thr220Ala, in the RACGAP1 gene. Both patients presented with macrocytic anemia, aberrant multinucleated erythroblasts in the bone marrow typically seen in CDA III cases, no iron overload and skull defects secondary to severe anemia. Silencing of RACGAP1 using siRNA in HeLa cells mimics the cytokinesis defect observed in the bone marrow of our patients. Both mutations disrupt normal cytokinesis and alter the GTPase balance in patients' cells. We conclude that the autosomal recessive form of CDA type III is caused by mutations in the RACGAP1 gene, encoding for RACGAP1 protein, which is the partner of MKLP1 in the centralspindlin complex critical for cytokinesis and now both proteins are associated with CDA type III. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

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Characterization of the interactions between Codanin-1 and C15Orf41, two proteins implicated in Congenital dyserythropoietic anemia type I disease

10.21203/rs.2.17570/v1 ◽

2019 ◽

Author(s):

Grace Swickley ◽

Yehoshua Bloch ◽

Lidor Malka ◽

Adi Meiri ◽

Sharon Noy-Lotan ◽

...

Keyword(s):

Phylogenetic Analyses ◽

3D Structure ◽

Macrocytic Anemia ◽

Extreme Case ◽

Etiologic Factor ◽

Physical Interaction ◽

Type I ◽

Homologous Proteins ◽

Congenital Dyserythropoietic Anemia ◽

Major Function

Abstract Background Congenital dyserythropoietic anemia type I (CDA I), is an autosomal recessive disease with macrocytic anemia in which erythroid precursors in the bone marrow exhibit pathognomonic abnormalities including spongy heterochromatin and chromatin bridges. We have shown previously that the gene mutated in CDA I encodes Codanin-1, a ubiquitously expressed and evolutionarily conserved large protein. Recently, an additional etiologic factor for CDA I was reported, C15Orf41, a predicted nuclease. Mutations in both CDAN1 and C15Orf41 genes results in very similar erythroid phenotype. However, the possible relationships between these two etiologic factors is not clear. the sequence of Codanin-1 protein does not resemble any known protein.Results We demonstrate here that Codanin-1 and C15Orf41 bind to each other, and that Codanin-1 stabilizes C15Orf41. C15Orf41 protein is mainly nuclear and Codanin-1 overexpression shifts it to the cytoplasm. Phylogenetic analyses demonstrated that even though Codanin-1 is an essential protein in mammals, it was lost from several diverse and unrelated animal taxa. Interestingly, C15Orf41 was eliminated in the exact same animal taxa. This is an extreme case of the Phylogenetic Profiling phenomenon, which strongly suggests common pathways for these two proteins. Lastly, as the 3D structure is more conserved through evolution than the protein sequence, we have used the Phyre2 alignment program to find structurally homologous proteins. We found that Codanin-1 is highly similar to CNOT1, a conserved protein which serves as a scaffold for proteins involved in mRNA stability and transcriptional control. Conclusions The physical interaction and the stabilization of C15Orf41 by Codanin-1, combined with the phylogenetic co-existence and co-loss of these two proteins during evolution, suggest that the major function of the presumptive scaffold protein, Codanin-1, is to regulate C15Orf41 activities. The similarity between Codanin-1 and CNOT1 suggest that Codanin-1 is involved in RNA metabolism and activity, and opens up a new avenue for the study of the molecular pathways affected in CDAI.

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Characterization of the interactions between Codanin-1 and C15Orf41, two proteins implicated in Congenital dyserythropoietic anemia type I disease

10.21203/rs.2.17570/v2 ◽

2020 ◽

Author(s):

Grace Swickley ◽

Yehoshua Bloch ◽

Lidor Malka ◽

Adi Meiri ◽

Sharon Noy-Lotan ◽

...

Keyword(s):

Phylogenetic Analyses ◽

3D Structure ◽

Macrocytic Anemia ◽

Extreme Case ◽

Etiologic Factor ◽

Physical Interaction ◽

Type I ◽

Homologous Proteins ◽

Congenital Dyserythropoietic Anemia ◽

Major Function

Abstract Background Congenital dyserythropoietic anemia type I (CDA I), is an autosomal recessive disease with macrocytic anemia in which erythroid precursors in the bone marrow exhibit pathognomonic abnormalities including spongy heterochromatin and chromatin bridges. We have shown previously that the gene mutated in CDA I encodes Codanin-1, a ubiquitously expressed and evolutionarily conserved large protein. Recently, an additional etiologic factor for CDA I was reported, C15Orf41, a predicted nuclease. Mutations in both CDAN1 and C15Orf41 genes results in very similar erythroid phenotype. However, the possible relationships between these two etiologic factors is not clear. Results We demonstrate here that Codanin-1 and C15Orf41 bind to each other, and that Codanin-1 stabilizes C15Orf41. C15Orf41 protein is mainly nuclear and Codanin-1 overexpression shifts it to the cytoplasm. Phylogenetic analyses demonstrated that even though Codanin-1 is an essential protein in mammals, it was lost from several diverse and unrelated animal taxa. Interestingly, C15Orf41 was eliminated in the exact same animal taxa. This is an extreme case of the Phylogenetic Profiling phenomenon, which strongly suggests common pathways for these two proteins. Lastly, as the 3D structure is more conserved through evolution than the protein sequence, we have used the Phyre2 alignment program to find structurally homologous proteins. We found that Codanin-1 is highly similar to CNOT1, a conserved protein which serves as a scaffold for proteins involved in mRNA stability and transcriptional control. Conclusions The physical interaction and the stabilization of C15Orf41 by Codanin-1, combined with the phylogenetic co-existence and co-loss of these two proteins during evolution, suggest that the major function of the presumptive scaffold protein, Codanin-1, is to regulate C15Orf41 activities. The similarity between Codanin-1 and CNOT1 suggest that Codanin-1 is involved in RNA metabolism and activity, and opens up a new avenue for the study of the molecular pathways affected in CDAI.

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Clinical features and studies of erythropoiesis in Israeli Bedouins with congenital dyserythropoietic anemia type I

Blood ◽

10.1182/blood.v87.5.1763.1763 ◽

1996 ◽

Vol 87 (5) ◽

pp. 1763-1770 ◽

Cited By ~ 44

Author(s):

H Tamary ◽

H Shalev ◽

D Luria ◽

D Shaft ◽

M Zoldan ◽

...

Keyword(s):

Chromatin Condensation ◽

Macrocytic Anemia ◽

High Ratio ◽

Beta Thalassemia ◽

Unknown Etiology ◽

Type I ◽

Serological Tests ◽

Congenital Dyserythropoietic Anemia ◽

Ultrastructural Studies ◽

Erythroid Precursors

Abstract Congenital dyserythropoietic anemia (CDA) type I is a rare macrocytic anemia of unknown etiology. In the present study, we redefined the clinical and laboratory picture of CDA type I, some of its pathogenic aspects, and the association with thalassemia-like features in 20 patients, all of whom belong to one Bedouin tribal group and are probably descended from a common ancestor. In each case ultrastructural studies of bone marrow (BM) erythroblasts showed the classic morphological findings of CDA type I. Serological tests for CDA type II were negative. The clinical picture was variable, but mostly benign. Some patients displayed elevated hemoglobin A2 levels or high ratio of alpha- to non-alpha- globin. However, neither family studies nor complete sequence analysis of the beta-globin was compatible with beta- thalassemia. Increased erythropoiesis was manifested by a high number of BM erythroid burst-forming units. Serum erythropoietin was also elevated. BM flow cytometry studies demonstrated arrest of erythroid precursors in the S phase of the cell cycle. The ultrastructural morphological features of the erythroid precursors, showing peripheral chromatin condensation, suggest apoptosis. Additional studies are indicated to define the molecular basis of this disease.

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Structural basis for inhibition of the histone chaperone activity of SET/TAF-Iβ by cytochrome c

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1508040112 ◽

2015 ◽

Vol 112 (32) ◽

pp. 9908-9913 ◽

Cited By ~ 27

Author(s):

Katiuska González-Arzola ◽

Irene Díaz-Moreno ◽

Ana Cano-González ◽

Antonio Díaz-Quintana ◽

Adrián Velázquez-Campoy ◽

...

Keyword(s):

Dna Damage ◽

Death Receptor ◽

Structural Features ◽

Histone Chaperone ◽

Chaperone Activity ◽

New Drugs ◽

Structural Basis ◽

Histone Chaperones ◽

Nucleosome Assembly ◽

Cell Nuclei

Chromatin is pivotal for regulation of the DNA damage process insofar as it influences access to DNA and serves as a DNA repair docking site. Recent works identify histone chaperones as key regulators of damaged chromatin’s transcriptional activity. However, understanding how chaperones are modulated during DNA damage response is still challenging. This study reveals that the histone chaperone SET/TAF-Iβ interacts with cytochrome c following DNA damage. Specifically, cytochrome c is shown to be translocated into cell nuclei upon induction of DNA damage, but not upon stimulation of the death receptor or stress-induced pathways. Cytochrome c was found to competitively hinder binding of SET/TAF-Iβ to core histones, thereby locking its histone-binding domains and inhibiting its nucleosome assembly activity. In addition, we have used NMR spectroscopy, calorimetry, mutagenesis, and molecular docking to provide an insight into the structural features of the formation of the complex between cytochrome c and SET/TAF-Iβ. Overall, these findings establish a framework for understanding the molecular basis of cytochrome c-mediated blocking of SET/TAF-Iβ, which subsequently may facilitate the development of new drugs to silence the oncogenic effect of SET/TAF-Iβ’s histone chaperone activity.

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Molecular Basis of Congenital Dyserythropoietic Anemia Type I in French Patients.

Blood ◽

10.1182/blood.v104.11.3709.3709 ◽

2004 ◽

Vol 104 (11) ◽

pp. 3709-3709 ◽

Cited By ~ 1

Author(s):

Hannah Tamary ◽

Orly Dgany ◽

Alexis Proust ◽

Tanya Krasnov ◽

Nili Avidan ◽

...

Keyword(s):

Severe Disease ◽

Macrocytic Anemia ◽

Monozygotic Twin ◽

Type I ◽

Missense Mutations ◽

Novel Mutations ◽

Gene Encoding ◽

Congenital Dyserythropoietic Anemia ◽

Number Of Patients ◽

Genotype Correlation

Abstract Congenital dyserythropoietic anemia type I (CDA I) is an inherited disorder characterized by macrocytic anemia and occasionally also by distal bone malformations. The disease has recently been shown to be caused by mutations in the CDAN1 gene, encoding codanin-1. The aim of the study was to characterize the CDAN1 mutations in 12 French patients with CDA I. The clinical data of the 12 French patients (10 kindreds) with CDA I were reviewed. Each of the 28 CDAN1 exons was amplified and sequenced. Half of the patients had a severe disease with prominent neonatal manifestations, complex bone disease, or both. Nine disease-causing mutations were identified: 6 described previously (P1130L, P671L, F869I, R681X, R713W, S1034F) and 3 novel mutations (R687W, F52L and IVS 8 G to A). Seven were missense mutations located in exons 14 to 28. Twenty seven per cent were identified in exon 14. No patient was homozygous for null type mutations. Only in two monozygotic twin patients did we fail to uncover a mutation. Mutations P671L, F52L and R713W were found on four, two and two alleles, respectively. One of the P671L alleles carried a second mutation (R687W). In conclusion the CDAN1 gene is apparently involved in most cases of CDA I in the French patients explored. Our study supports the previous findings that homozygosity for the null type mutations may be lethal, and that CDAN1 mutations are localized mainly in exons 12–28. In the present small group of patients, no apparent phenotype-genotype correlations were observed, in particular concerning abnormalities of the bones. Analysis of a larger number of patients from different ethnic groups is required to further characterize phenotype-genotype correlation in CDA I.

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