Loss of Dynamin 2 GTPase function results in microcytic anaemia

Fiona 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

Research output: Contribution to journalArticleResearchpeer-review

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.
Original languageEnglish
Pages (from-to)616 - 628
Number of pages13
JournalBritish Journal of Haematology
Volume178
Issue number4
DOIs
Publication statusPublished - Sep 2017

Keywords

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

Cite this

Brown, Fiona ; Collett, Michael ; Tremblay, Cedric S. ; Rank, Gerhard ; De Camilli, Pietro ; Booth, Carmen J. ; Bitoun, Marc ; Robinson, Phillip J ; Kile, Benjamin T. ; Jane, Stephen M. ; Curtis, David J. / Loss of Dynamin 2 GTPase function results in microcytic anaemia. In: British Journal of Haematology. 2017 ; Vol. 178, No. 4. pp. 616 - 628.
@article{e895c7b8fd6f44c7a9896ae65da52199,
title = "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 microcytichypochromia caused by a V235G missense mutation in Dynamin 2(Dnm2). Mutations in Dnm2, a GTPase, are highly disease-specific andhave been implicated in four forms of human diseases: centronuclearmyopathy, 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 anessential mediator of clathrin-mediated endocytosis, which is required forthe 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 = "microcytic anaemia, Dynamin 2 mutation, clathrin-mediated endocytosis, ethylnitrosurea mutagenesis, mouse model of anaemia",
author = "Fiona Brown and Michael Collett and Tremblay, {Cedric S.} and Gerhard Rank and {De Camilli}, Pietro and Booth, {Carmen J.} and Marc Bitoun and Robinson, {Phillip J} and Kile, {Benjamin T.} and Jane, {Stephen M.} and Curtis, {David J.}",
year = "2017",
month = "9",
doi = "10.1111/bjh.14709",
language = "English",
volume = "178",
pages = "616 -- 628",
journal = "British Journal of Haematology",
issn = "0007-1048",
publisher = "John Wiley & Sons",
number = "4",

}

Loss of Dynamin 2 GTPase function results in microcytic anaemia. / Brown, Fiona; Collett, Michael; Tremblay, Cedric S.; Rank, Gerhard; De Camilli, Pietro; Booth, Carmen J.; Bitoun, Marc; Robinson, Phillip J; Kile, Benjamin T.; Jane, Stephen M.; Curtis, David J.

In: British Journal of Haematology, Vol. 178, No. 4, 09.2017, p. 616 - 628.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Loss of Dynamin 2 GTPase function results in microcytic anaemia

AU - Brown, Fiona

AU - Collett, Michael

AU - Tremblay, Cedric S.

AU - Rank, Gerhard

AU - De Camilli, Pietro

AU - Booth, Carmen J.

AU - Bitoun, Marc

AU - Robinson, Phillip J

AU - Kile, Benjamin T.

AU - Jane, Stephen M.

AU - Curtis, David J.

PY - 2017/9

Y1 - 2017/9

N2 - In a dominant mouse ethylnitrosurea mutagenesis screen for genes regulating erythropoiesis, we identified a pedigree with a novel microcytichypochromia caused by a V235G missense mutation in Dynamin 2(Dnm2). Mutations in Dnm2, a GTPase, are highly disease-specific andhave been implicated in four forms of human diseases: centronuclearmyopathy, 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 anessential mediator of clathrin-mediated endocytosis, which is required forthe 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.

AB - In a dominant mouse ethylnitrosurea mutagenesis screen for genes regulating erythropoiesis, we identified a pedigree with a novel microcytichypochromia caused by a V235G missense mutation in Dynamin 2(Dnm2). Mutations in Dnm2, a GTPase, are highly disease-specific andhave been implicated in four forms of human diseases: centronuclearmyopathy, 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 anessential mediator of clathrin-mediated endocytosis, which is required forthe 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.

KW - microcytic anaemia

KW - Dynamin 2 mutation

KW - clathrin-mediated endocytosis

KW - ethylnitrosurea mutagenesis

KW - mouse model of anaemia

U2 - 10.1111/bjh.14709

DO - 10.1111/bjh.14709

M3 - Article

VL - 178

SP - 616

EP - 628

JO - British Journal of Haematology

JF - British Journal of Haematology

SN - 0007-1048

IS - 4

ER -