<i>RACGAP1</i> variants in a sporadic case of CDA III implicate the dysfunction of centralspindlin as the basis of the disease
Sandeep N. Wontakal, Mishan Britto, Huan Zhang, Yongshuai Han, Chengjie Gao, Sarah Tannenbaum, Benjamin H. Durham, Margaret T. Lee, Xiuli An, Masanori Mishima
Abstract
Congenital dyserythropoietic anemias (CDAs) are rare disorders defined by morphologic abnormalities of erythroid precursors that lead to ineffective erythropoiesis. 1,2 CDA type III (CDA III), characterized by multinucleated erythroblasts in the bone marrow, represents the rarest form, with only 60 patients described in the literature. Studies in 2 independent families identified a causative dominant missense mutation in KIF23, which encodes MKLP1, 3 the kinesin subunit of centralspindlin, a key regulator of cytokinesis. In addition to the familial cases, a few sporadic cases of CDA III have been reported indicating an autosomal recessive pattern of inheritance. 1,2 However, no genetic cause has been identified in such cases. Here, we describe a sporadic CDA III case associated with compound heterozygous variants in RACGAP1, which encodes CYK4/MgcRac-GAP, the other subunit of centralspindlin. We demonstrate these variants cause cytokinesis failure in human erythroid cells as a result of altered target specificity in Rho-family GTPase signaling.