Recapitulation of erythropoiesis in congenital dyserythropoietic anaemia type I (CDA-I) identifies defects in differentiation and nucleolar abnormalities
The investigation of inherited disorders of erythropoiesis has elucidated many of the principles underlying the production of normal red blood cells and how this is perturbed in human disease. Congenital Dyserythropoietic Anaemia type 1 (CDA-I) is a rare form of anaemia caused by mutations in two ge...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
| Published: |
Ferrata Storti Foundation
2020
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| Summary: | The investigation of inherited disorders of erythropoiesis has elucidated many of the
principles underlying the production of normal red blood cells and how this is
perturbed in human disease. Congenital Dyserythropoietic Anaemia type 1 (CDA-I)
is a rare form of anaemia caused by mutations in two genes of unknown function:
CDAN1 and CDIN1 (previously called C15orf41), whilst in some cases, the
underlying genetic abnormality is completely unknown. Consequently, the pathways
affected in CDA-I remain to be discovered. To enable detailed analysis of this rare
disorder we have validated a culture system which recapitulates all of the cardinal
haematological features of CDA-I, including the formation of the pathognomonic
‘spongy’ heterochromatin seen by electron microscopy. Using a variety of cell and
molecular biological approaches we discovered that erythroid cells in this condition
show a delay during terminal erythroid differentiation, associated with increased
proliferation and widespread changes in chromatin accessibility. We also show that
the proteins encoded by CDAN1 and CDIN1 are enriched in nucleoli which are
structurally and functionally abnormal in CDA-I. Together these findings provide
important pointers to the pathways affected in CDA-I which for the first time can now
be pursued in the tractable culture system utilised here. |
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