Monash study reveals mutation linked to anaemia

A/Prof David Curtis and Dr Ashlee Conway during her candidature
at the Australian Centre for Blood Diseases

by Anne Crawford

Monash University researchers have identified a new mutation in a gene responsible for a process that is vital to developing the blood cells that absorb iron and generate haemoglobin. The mutation results in anaemia similar to that of an iron-deficiency.

The researchers, in the Red Cell team at the Australian Centre for Blood Diseases (ACBD), revealed the mutation in the TFRC gene, which encodes for the Transferrin Receptor, the body’s main iron receptor.


Mutations in this gene result in circulating red blood cells that are much smaller than average and contain less haemoglobin, meaning they are less efficient at transporting oxygen around the body.

The study, published in Blood Advances, found in mouse models that different mutations within the TFRC gene can affect the iron receptor in different ways, and therefore result in various degrees of anaemia, some more severe than others.

The researchers used randomly-mutated mice as a platform to identify new genes which may be responsible for blood formation.

“We confirmed that this gene is absolutely essential for life; mice cannot survive very long without it due to a lack of blood formation,” first author Dr Ashlee Conway said.

“One new mutation that we identified within the TFRC gene was very different from others that we had studied before,” Dr Conway said. “In most cases, mutations of this gene delete the receptor entirely, but this new mutation kept the receptor in place and instead distorted its ability to bind and engulf iron into the cell,” she said.

Using a new method of cell analysis, the researchers were able to watch iron fail to enter into these blood cells because of the faulty receptor. “It was actually pretty amazing to watch for the first time; I don’t think the absorption of iron into an individual blood cell has been captured before in the way we were able to observe it.”

Dr Conway said the findings have broadened the understanding of the iron metabolism pathway in blood, and demonstrate there was more than one way that this iron receptor caused anaemia when defective.

The researchers found the anaemia could not be treated in the mice using common therapies. “Typical iron-boosting medications are useless in this instance,” Dr Conway said.

Mutations in the TFRC gene have not been definitively linked to anaemia in humans, however many patients with unexplainable iron-deficiency-like symptoms continuously go undiagnosed and present symptoms that closely match those of the mutant mice, she said. “This may explain why similar iron therapies sometimes fail to alleviate anaemia in some patients.”

The researchers, led by Professor David Curtis, found that a simple diagnostic test – an alteration of a pre-existing blood test – may be more accurate in detecting iron-deficient red blood cells in patients.

The study was part of a Red Cell project that has spanned more than a decade, resulting in the identification of many interesting new genes that are indispensable for healthy blood cell development in mice and humans.

“Often these discovery projects find new functions of a pre-existing gene, which may not have been previously known to contribute to blood cells, and at other times result in the generation of a mouse model of a known human blood disease, giving us the opportunity to test possible new treatments which may benefit humans with a similar condition,” Dr Conway said.

Dr Conway participated in the Red Cell project as part of her PhD, supervised by Associate Professor David Curtis (ABCD) and Professor Steve Jane (Medicine). In May this year she took up a position as a Research Fellow in the Harvard Stem Cell group, in the Hematology/Oncology department of the Boston Children’s Hospital.

“I’m still working to further understand healthy blood cell development, to ultimately find better treatments for blood and bone marrow diseases in children.”

She said she hoped to stay at Harvard University for about five years. “I love the ACBD and I do hope to return one day, hopefully to broaden their non-malignant haematology research teams.”

Dr Conway was initially on a path to studying immunology but became fascinated by clinical haematology when she first met Professor Stephen Jane, Head of the Central Clinical School, during her last year as an undergraduate student at Monash. (Professor Jane is also an author on this paper.)

“After spending an Honours year in his lab, I was absolutely hooked on blood, and still am!

“I moved to the US to study paediatric blood diseases, since there is just a larger population and greater variety of conditions here to work with. There are certainly some incredibly fascinating rare blood and bone marrow diseases that remain understudied; every little endeavour counts,” she said.

Reference
Conway AJ, Brown FC, Rank G, Kile BT, Morton CJ, Jane SM, Curtis DJ. Characterization of Tfrc-mutant mice with microcytic phenotypes. Blood Adv. 2018 Aug 14;2(15):1914-1922. doi: 10.1182/bloodadvances.2018018820.