Contributions
This abstract is embargoed until Saturday, June 12, 09:00 CEST
Abstract: S272
Type: Oral Presentation
Session title: Changing the scene on congenital anemias
Background
Congenital Dyserythropoietic Anemia (CDA) Type III was first described in a Swedish family as a disease with a dominant hereditary pattern caused by mutations in the KIF23 gene, whose protein product is involved in cytokinesis. Despite this, there are several reports of an autosomal recessive inheritance form of CDA III with no identified genetic cause.
Aims
To identify the genetic origin of the recessive forms of Congenital Dyserythropoietic Anemia (CDA) Type III
Methods
Gene variant analysis using WES sequencing coupled with siRNA silencing and microscopy studies. CRISPR/Cas9 technology to generate knock-in models in zebrafish and knock-out cellular models.
Results
Here we report a young Spanish case clinically diagnosed of CDA III with no mutations in any of the known CDA genes, including KIF23 gene. His bone marrow aspirate showed the typical phenotype of CDA III with giant multinucleated erythroblasts, giant hyperlobulated erythroblast, inter-cytoplasmatic bridges and chromatin bridges. The rest of the family was unaffected pointing to a possible recessive form of CDA III. The family was analyzed by WES and a pathogenic rare missense mutation was identified in homozygosis in the proband; while the rest of the family (father, mother and unaffected sister) were heterozygous.
Silencing of the identified gene in HeLa cells mimics the phenotype observed in the bone marrow of our patient. Complete abrogation of this gene in zebrafish shows defects in cytokinesis and erythropoiesis and showing a clear anemic phenotype. The protein product of this gene has a role in cytokinesis and it is highly expressed in erythroid cells.
Conclusion
All these evidences indicate that we have identified a new gene responsible for an autosomal recessive form of CDA type III. We are currently generating a knock-in zebrafish models with the same mutation as the one presented in our patient, as well as sequencing additional possible CDA type III cases.
Keyword(s): Anemia, Erythropoieisis, Iron
This abstract is embargoed until Saturday, June 12, 09:00 CEST
Abstract: S272
Type: Oral Presentation
Session title: Changing the scene on congenital anemias
Background
Congenital Dyserythropoietic Anemia (CDA) Type III was first described in a Swedish family as a disease with a dominant hereditary pattern caused by mutations in the KIF23 gene, whose protein product is involved in cytokinesis. Despite this, there are several reports of an autosomal recessive inheritance form of CDA III with no identified genetic cause.
Aims
To identify the genetic origin of the recessive forms of Congenital Dyserythropoietic Anemia (CDA) Type III
Methods
Gene variant analysis using WES sequencing coupled with siRNA silencing and microscopy studies. CRISPR/Cas9 technology to generate knock-in models in zebrafish and knock-out cellular models.
Results
Here we report a young Spanish case clinically diagnosed of CDA III with no mutations in any of the known CDA genes, including KIF23 gene. His bone marrow aspirate showed the typical phenotype of CDA III with giant multinucleated erythroblasts, giant hyperlobulated erythroblast, inter-cytoplasmatic bridges and chromatin bridges. The rest of the family was unaffected pointing to a possible recessive form of CDA III. The family was analyzed by WES and a pathogenic rare missense mutation was identified in homozygosis in the proband; while the rest of the family (father, mother and unaffected sister) were heterozygous.
Silencing of the identified gene in HeLa cells mimics the phenotype observed in the bone marrow of our patient. Complete abrogation of this gene in zebrafish shows defects in cytokinesis and erythropoiesis and showing a clear anemic phenotype. The protein product of this gene has a role in cytokinesis and it is highly expressed in erythroid cells.
Conclusion
All these evidences indicate that we have identified a new gene responsible for an autosomal recessive form of CDA type III. We are currently generating a knock-in zebrafish models with the same mutation as the one presented in our patient, as well as sequencing additional possible CDA type III cases.
Keyword(s): Anemia, Erythropoieisis, Iron