Format

Send to

Choose Destination
Br J Haematol. 2017 Aug;178(4):616-628. doi: 10.1111/bjh.14709. Epub 2017 May 3.

Loss of Dynamin 2 GTPase function results in microcytic anaemia.

Author information

1
Australian Centre for Blood Diseases, Central Clinical School, Monash University and Alfred Health, Melbourne, Vic., Australia.
2
Cell Signalling Unit, Children's Medical Research Institute, The University of Sydney, Sydney, NSW, Australia.
3
Rotary Bone Marrow Research Laboratory, Royal Melbourne Hospital, Melbourne, Vic., Australia.
4
Departments of Neuroscience and Cell Biology, Howard Hughes Medical Institute, Kavli Institute for Neuroscience, Yale University School of Medicine, New Haven, CT, USA.
5
Section of Comparative Medicine, Yale University School of Medicine, New Haven, CT, USA.
6
Research Centre for Myology, UPMC Univ Paris 06 and INSERM UMRS 974, CNRS FRE 3617, Institute of Myology, Paris, France.
7
The Walter and Eliza Hall Institute of Medical Research, Melbourne, Vic., Australia.

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.

KEYWORDS:

Dynamin 2 mutation; clathrin-mediated endocytosis; ethylnitrosurea mutagenesis; microcytic anaemia; mouse model of anaemia

PMID:
28466468
DOI:
10.1111/bjh.14709
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Wiley
Loading ...
Support Center