hypochromia caused by a V235G missense mutation in Dynamin 2
(Dnm2). Mutations in Dnm2, a GTPase, are highly disease-specific and
have been implicated in four forms of human diseases: centronuclear
myopathy, Charcot-Marie Tooth neuropathy and, more recently, T-cell leukaemia and Hereditary Spastic Paraplegia, but red cell abnormalities have not been reported to date. The V235G mutation lies within a crucial GTP nucleotide-binding pocket of Dnm2, and resulted in defective GTPase activity and incompatibility with life in the homozygous state. Dnm2 is an
essential mediator of clathrin-mediated endocytosis, which is required for
the uptake of transferrin (Tf) into red cells for incorporation of haem.
Accordingly, we observed significantly reduced Tf uptake by Dnm2+/V235G cells, which led to impaired endosome formation. Despite these deficiencies, surprisingly all iron studies were unchanged, suggesting an unexplained alternative mechanism underlies microcytic anaemia in Dnm2+/V235G mice. This study provides the first in vivo evidence for the requirements of Dnm2 in normal erythropoiesis.
- microcytic anaemia
- Dynamin 2 mutation
- clathrin-mediated endocytosis
- ethylnitrosurea mutagenesis
- mouse model of anaemia