Award Title: Investigating the role of transcription factor GATA1 in Diamond-Blackfan anaemia pathogenesis and diagnosis
Funder: Action Medical Research

Abstract: Background _x000D_
Diamond-Blackfan anaemia (DBA) is a very rare inherited condition, usually diagnosed within the first year of life and characterised by severe anaemia. Anaemia is a condition where there are too few red blood cells in the blood and therefore not enough oxygen can be carried around the body. This results in persistent tiredness and other symptoms such as breathlessness, headache, rapid heartbeat and difficulty in concentrating. Around half of children with DBA also have physical changes - they are often short for their age and may have delayed puberty. There is presently no cure for DBA and long-term treatment involving regular blood transfusions or steroid drugs can cause complications. Around 70 per cent of children with DBA have been found to have faulty genes affecting the ribosomes, tiny structures found in all cells which make new proteins. These gene changes (or mutations) cause impaired synthesis of a protein, GATA1, which is essential for the production of new red blood cells. Inadequate levels of this protein result in anaemia. However, this explanation does not account for the 30 per cent of children with DBA who do not have ribosomal gene mutations. In addition, rare mutations in the GATA1 gene itself have been also been identified in DBA patients, further highlighting the critical involvement of this protein in DBA. _x000D_
_x000D_
The research project_x000D_
These researchers have provided evidence suggesting that, as part of its role in red blood cell production, the GATA1 protein may also control genes that are responsible for the production of ribosomes themselves. They now plan to investigate directly the possibility that GATA1 controls ribosome production in red blood cells and to test their prediction that rare mutations in the GATA1 gene could impact on ribosome production and lead to DBA. The team will also explore the development of a new diagnostic test to identify mutations in GATA1-controlled ribosomal genes that may account for some of the undiagnosed DBA cases. This work will improve our understanding of the causes of anaemia in DBA and could ultimately lead to new treatments and improved diagnosis for children who do not currently have a confirmed genetic explanation. _x000D_

Lay Abstract: Background _x000D_
Diamond-Blackfan anaemia (DBA) is a very rare inherited condition, usually diagnosed within the first year of life and characterised by severe anaemia. Anaemia is a condition where there are too few red blood cells in the blood and therefore not enough oxygen can be carried around the body. This results in persistent tiredness and other symptoms such as breathlessness, headache, rapid heartbeat and difficulty in concentrating. Around half of children with DBA also have physical changes - they are often short for their age and may have delayed puberty. There is presently no cure for DBA and long-term treatment involving regular blood transfusions or steroid drugs can cause complications. Around 70 per cent of children with DBA have been found to have faulty genes affecting the ribosomes, tiny structures found in all cells which make new proteins. These gene changes (or mutations) cause impaired synthesis of a protein, GATA1, which is essential for the production of new red blood cells. Inadequate levels of this protein result in anaemia. However, this explanation does not account for the 30 per cent of children with DBA who do not have ribosomal gene mutations. In addition, rare mutations in the GATA1 gene itself have been also been identified in DBA patients, further highlighting the critical involvement of this protein in DBA. _x000D_
_x000D_
The research project_x000D_
These researchers have provided evidence suggesting that, as part of its role in red blood cell production, the GATA1 protein may also control genes that are responsible for the production of ribosomes themselves. They now plan to investigate directly the possibility that GATA1 controls ribosome production in red blood cells and to test their prediction that rare mutations in the GATA1 gene could impact on ribosome production and lead to DBA. The team will also explore the development of a new diagnostic test to identify mutations in GATA1-controlled ribosomal genes that may account for some of the undiagnosed DBA cases. This work will improve our understanding of the causes of anaemia in DBA and could ultimately lead to new treatments and improved diagnosis for children who do not currently have a confirmed genetic explanation. _x000D_

Research Activity Codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health Categories: BLOOD