Achille Iolascon, MD, PhD - "Dyserythropoietic anemias from the microscope to the sequence"
Jan 25, 2017
from 12:00 PM to 01:30 PM
|Where||Tigem, Auditorium "Vesuvius"|
|Contact Name||Andrea Ballabio|
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Erythropoiesis is the complex process that involves differentiation of early erythroid progenitors to mature enucleated red cells. Dyserythropoiesis is a derangement along this process and usually it causes a reduced capacity of cell production. Since this process is accompanied by anemia, it causes an increased erythropoietic signal that causes an enhanced presence of bone marrow erythroid cells.
Dyserythropoiesis may represent a physiological condition or an inherited or acquired disease.
All inherited dyserythropoiesis forms have in common bone marrow erythroid abnormality and erythroid hyperplasia appearance. Three classical types of CDAs have been defined on the basis of bone marrow morphology and this working classification is still used in clinical practice. Both CDA I and II are autosomal recessive diseases. The hallmark of CDA I are macrocytic anemia and bone marrow appearance of incompletely divided cells with thin chromatin bridges between pairs of erythroblasts, which may also be seen between two nuclei in a single cell. On the contrary CDA II patients show a marked increase in bi- and multi-nucleated erythroblasts in their bone marrow.
CDA type III is an autosomal dominant disease with giant multi-nucleated erythroblasts in bone marrow and it appears extremely rare. This latter was first reported in 1962 in a large Swedish family accounting for 34 patients. The causative gene, Kif23, was mapped on chromosome 15. There are, however, families that fall within the general definition of the CDAs, but do not conform to any of the three classical types. CDA type IV, a CDA II with negative serum tests, sharing similar bone marrow morphology of CDA III (multi-nucleated erythroblasts), was originally listed in the group of the CDA variants. Mutations in erythroid transcription factor genes (KLF1, GATA-1) have been recently identified as possible causative genes.
The CDA I and II combined prevalence varied widely between European regions, with minimal values of 0.08 cases/ million in Scandinavia and 2.60 cases/million in Italy. CDA II is more frequent than CDA I, with an overall ratio of approximately 3.2, but the ratio also varied between different regions. The estimations reported are most probably below the true prevalence rates, due to failure to make the correct diagnosis and to underreporting.
The gene responsible for CDA I (CDAN1 gene) was mapped to the long arm of chromosome 15 between 15q15.1q15.3 by homozygosity mapping performed.The CDAN1 gene was successively cloned with 28 exons spanning 15 Kb and encoding a protein named codanin-1. In unrelated patients of European, Bedouin and Asian origin, different point mutations were detected. Approximately 90% of patients with a bone marrow suggesting CDA I have codanin-1 gene mutations. All these seem to be independent events and up to now no particularly frequent mutations are present in literature data. Interestingly, no homozygotes or compound heterozygotes for null-type mutations have been identified, supporting an earlier notion that codanin-1 may have a unique function and may be essential during development. Codanin-1 is a ubiquitously expressed protein, still not well characterized. It seems to be related to chromosome structure and it must be involved in mitotic process.
Very recently several families CDAN1 mutation negative allowed for the identification of a new causative gene: C15ORF41, coding for a protein involved in DNA replication and chromatin assembly.
Sequencing analysis of CDA II patients showed a wide spectrum of different mutations in SEC23B gene in either the compound heterozygous or homozygous state. The disease gene encodes the cytoplasmic coat protein (COP)II component SEC23B, involved in the secretory pathway of eukaryotic cells. COPII is a multi-subunit complex which mediates accumulation of secretory cargo, deformation of the membrane and generation of subsequent anterograde transport of correctly folded cargo that bud from the ER towards the Golgi apparatus. The specificity of the CDA II phenotype seems to be determined by tissue-specific expression of SEC23B versus SEC23A during erythroid differentiation.
An attempt to identify a genotype-phenotype relationship demonstrated that patients with compound heterozygosity for a missense and nonsense mutation tended to produce more severe clinical presentations than homozygosity or compound heterozygosity for two missense mutations. Homozygosity or compound heterozygosity for two nonsense mutations was never found, and it was supposed to be lethal. Very recently Sec23b deficient mice was generated and it has not apparentanemia phenotype, but die shortly after birth, with degeneration of professional secretory tissues, pancreas as well as salivary glands. These data demonstrate that Sec23b deficient humans and mice exhibit disparate phenotypes, apparently restricted to CDA II in humans and a prominent neonatal pancreatic insufficiency in mice.
- 1. Heimpel H, Wendt F. Congenital dyserythropoietic anemia with karyorrhexis and multinuclearity of erythroblasts. Helv Med Acta 1968;34(2):103-115
- 2. Heimpel H et al. The morphological diagnosis of congenital dyserythropoietic anemia: results of a quantitative analysis of peripheral blood and bone marrow cells. Haematologica 2010;95(6):1034-1036.
3. Iolascon A. et al. Congenital dyserythropoietic anemias: molecular insights and diagnostic approach. Blood. 2013 Sep 26;122(13):2162-6.
4 Liljeholm M. et al. Congenital dyserythropoietic anemia type III (CDA III) is caused by a mutation in kinesin family member, KIF23. Blood 2013;121(23):4791-479
5 Wickramasinghe SN, Wood WG. Advances in the understanding of the congenital dyserythropoietic anaemias. Br J Haematol 2005;131(4):431-446
6 Dgany O. et al. Congenital dyserythropoietic anemia type I is caused by mutations in codanin-1. Am J Hum Genet 2002;71(6):1467-1474.
7 Noy-Lotan S. et al. Codanin-1, the protein encoded by the gene mutated in congenital dyserythropoietic anemia type I (CDAN1), is cell cycle-regulated. Haematologica 2009;94(5):629-637
8 Babbs C. et al. Homozygous mutations in a predicted endonuclease cause congenital dyserythropoietic anemia type I [published online ahead of print May 28, 2013]. Haematologica. 2013 Sep;98(9):1383-7
9 Schwarz K, Iolascon A et al. Mutations affecting the secretory COPII coat component SEC23B cause congenital dyserythropoietic anemia type II. Nat Genet 2009;41(8):936-940
10 Russo R.et al.Retrospective cohort study of 205 cases with congenital dyserythropoietic anemia type II: definition of clinical and molecular spectrum and identification of new diagnostic scores. Am J Hematol. 2014 Oct;89(10):169-75.
11 Tao J. et al. SEC23B is required for the maintenance of murine professional secretory tissues. Proc Natl Acad Sci USA 2012;109(29):E2001-E2009