The Novel Missense Mutation of GATA1 Caused Red Cell Adenosine Deaminase Overproduction Associated with Congenital Hemolytic Anemia

Red cell adenosine deaminase (ADA) overproduction (OMIM 102730) is a rare form of congenital hemolytic anemia. To date, only four independent families have been reported. Recently, we examined the red cell enzyme activities of an 18-year-old male Japanese patient with congenital hemolytic anemia, and diagnosed a new case of ADA overproduction. His ADA activity was measured as 39.7 IU/gHb, representing an over 30-fold elevation of the normal mean value. The patient's mother also showed a high red cell ADA, 7.40 IU/gHb, and the father had normal ADA activity. To elucidate the molecular basis of the elevated ADA activity, we performed a target-captured sequencing focusing on the 67 congenital-anemia related genes. The results showed that there was no structural mutation of ADA gene, and that the proband had a novel missense mutation of GATA1, c.920G>A, p.R307H. The proband was hemizygous, and the mother was heterozygous for the mutation. Subsequently, we examined a previously reported case of ADA overproduction, and identified the identical missense mutation of GATA1. These two cases had clinical similarities, such as low birth weight with hypospadias, splenomegaly, and slightly decreased platelet counts, suggesting that these cases could be categorized as X-linked anemia with or without neutropenia and/or platelet abnormality (XLANP, OMIM#300835). The previous case showed a rare blood type, Lu(a-b-) and a low beta/alpha globin synthetic ratio, whereas the present case depicted abnormal red cell morphology, such as stomatocytosis and target cells. Taken together, the missense mutation of GATA1 might cause the aberrant expression of erythroid-genes, inducing a short life-span of red cells.