Loss of Dynamin 2 GTPase function results in microcytic anaemia.

Abstract

In a dominant mouse ethylnitrosurea mutagenesis screen for genes regulating erythropoiesis, we identified a pedigree with a novel microcytic 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.

• Authors: Fiona C Brown, Michael Collett, Cedric S Tremblay, Gerhard Rank, Pietro De Camilli, Carmen J Booth, Marc Bitoun, Phillip J Robinson, Benjamin T Kile, Stephen M Jane, David J Curtis
• Journal: British journal of haematology (Br J Haematol) Vol. 178 Issue 4 Pg. 616-628 (08 2017) ISSN: 1365-2141 [Electronic] England
• PMID: 28466468 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2017 John Wiley & Sons Ltd.

Chemical References

• Transferrin
• Dynamin II

Topics

• Anemia, Hypochromic (blood, genetics)
• Animals
• Chromosome Mapping (methods)
• Disease Models, Animal
• Dynamin II (deficiency, genetics, physiology)
• Endocytosis (genetics, physiology)
• Erythrocytes (metabolism, pathology)
• Genotype
• High-Throughput Nucleotide Sequencing (methods)
• Mice, Knockout
• Mutation, Missense
• Transferrin (metabolism)