Mutations in the RACGAP1 gene cause autosomal recessive congenital dyserythropoietic anemia type III

Abstract

Congenital dyserythropoietic anemia type III (CDA III) is one of the rarest types of CDA. The autosomal dominant form of CDA III, is due to mono-allelic mutations in the KIF23 gene (MIM:105600); two such mutations described so far in a total of three families.1,2 KIF23 encodes mitotic kinesin-like protein (MKLP1), which dimerizes and combines with a homodimer of the RACGAP1 protein (Rac GTPase-activating protein 1), to form the centralspindlin complex regulating Rho GTPase activity and required for cytokinesis.3,4 Sporadic cases with CDA III pathology have been reported, suggesting a different genetic alteration.5 All reported CDA III cases present with a core phenotype consisting of variable degree of macrocytic anemia, signs of intravascular hemolysis, and giant multinucleated erythroblasts in the bone marrow. Additional symptoms such as multiple myeloma, monoclonal gammopathy, angioid streaks, hemosiderinuria, hepatosplenomegaly, iron overload or cirrhosis were described in some CDA III patients.6-9 Using next generation sequencing (NGS) in combination with ex vivo erythroid differentiation we identified two pathogenic missense mutations in the RACGAP1 gene in three unrelated families affected with the recessive form of CDA III.