Iron traffic gene variants in MS

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Iron traffic gene variants in MS

Postby Bethr » Thu Mar 17, 2011 6:02 pm

In light of the results from this abstract presented at IVDSN, I'd like to open up dialogue on these genes that control iron metabolism.
They cover different steps in iron metabolism, and influence each other, such as the HFE genes that have an effect on Hepcidin levels, lowering them and increasing iron uptake from the diet. Hepcidin is tightly tied in with T-lymphocytes. Recent studies suggest T-lymphocytes can also produce hepcidin. Big tie in there with the immune system. See
Human lymphocytes produce hepcidin that regulate iron levels in the body: Study
[url]
http://www.news-medical.net/news/201004 ... Study.aspx[/url]

Associated genes per the abstract:

Ferroportin FPN1-8GG
Increased MS risk if homozygous in all groups (especially SP)

Hepcidin HEPC 582GG
Increased risk if homozygous

Transferrin TF P5705
Homozygotes subtle risk to whole group

HFE H63D (hemochromatosis)
Homozygotes have increased progression especially in RRMS

These genes are not tested for regularly from what I can tell, except maybe the H63D hemochromatosis.
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Postby Bethr » Thu Mar 17, 2011 8:05 pm

Some details from a thesis on the subject:

Ferroportin FPN1-8GG
Increased MS risk if homozygous in all groups (especially SP)


Considering all cases and controls studied, 7.4% of MS cases and 1.7% of healthy matched controls were -8GG homozygous for the FPN1 -8GC gene variant with an overall OR-value of 4.9 (95%CI, 1.8-13.3; P=0.001) compared with wild-type -8CC reference genotype. This statistically indicates that the FPN1 -8GG homozygous genotype associated with an increased risk for MS of about five to seven-folds. Considering the patterns related with the course of MS disease, the risk was most evident in SP cases. PP cases fall short of significant result arising form fewer number of cases studied. Association of polymorphism in FPN1 related with MS insights a major role of iron overload and disease prognosis since this protein is expressed in a number of CNS port e.g. oligodendrocytes, neurons, astrocytes, and BBB-cells and plays a major role in extra and intra cellular iron trafficking (3). Till date no extensive studies have been done related with FPN1 gene mutation and its association with disease progression and susceptibility. The polymorphism in FPN1 may play a vital role in CNS physiology in variety of ways either enforcing anti efflux of iron from inside cell creating oxidative stress and cell death or producing molecular defects in FPN-IREs-IRPs machinery since in previous studies, there is mentioned one similar ferritin polymorphism that leads to hereditary hyperferritinemia (4).


Graphs available here http://air.unimi.it/bitstream/2434/64292/1/MIUR%20Thesis%20Report.doc
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Postby Cece » Fri Mar 18, 2011 11:56 am

This is all very interesting. It's something to have leads on what can distinguish a person's course between RR, SP, and PP.

In detail, by means a retrospective observational period
of ten years, those RR-patients carrying the -582G-allele had a higher chance to
progress in SP phenotype (log-rank; P=0.019).

It is noteworthy, that the number of -582GG homozygotes
increased considering the most severe MS clinical phenotypes (i.e. RR, 5.5%; SP,
11.0%; PP, 23.3%; P-trend=0.01).
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Postby Bethr » Sat Mar 19, 2011 7:25 am

I'm just going to research the FPN1 gene for the moment.
This I think is hemochromatosis type IV/Ferroportin disease and is supposedly very rare. Someone please correct me if necessary.
And from what I'm reading in the abstract, some patients in the study
were homozygous (double gene). You may only need one gene present to have an effect, ie: heterozygous. This FPN1 gene was only recently discovered, under 10 years ago.

This type of iron overload/hemochromatosis presents differently from the classic type 1 hemochromatosis. Ferroportin is the exporter of iron from the cells. In this type of iron disorder iron accumulates in the macrophages I believe.
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Postby Bethr » Sat Mar 19, 2011 8:18 am

This is a good explanation on the ferroportin link to brain iron.
Remembering that this type of iron overload disease would give you a low transferrin saturation, when the the classic Hemochromatosis will show high transferrin saturation (like I had prior to phlebotomy), so this is a different beast all together.




Wu, L.J. et al.




Expression of the iron transporter ferroportin in synaptic vesicles and the blood-brain barrier.

Iron homeostasis in the mammalian brain is an important and poorly understood subject. Transferrin-bound iron enters the endothelial cells of the blood-brain barrier from the systemic circulation, and iron subsequently dissociates from transferrin to enter brain parenchyma by an unknown mechanism. In recent years, several iron transporters, including the iron importer DMT1 (Ireg1, MTP, DCT1) and the iron exporter ferroportin (SLC11A3, Ireg, MTP1) have been cloned and characterized. To better understand brain iron homeostasis, we have characterized the distribution of ferroportin, the presumed intestinal iron exporter, and have evaluated its potential role in regulation of iron homeostasis in the central nervous system. We discovered using in situ hybridization and immunohistochemistry that ferroportin is expressed in the endothelial cells of the blood-brain barrier, in neurons, oligodendrocytes, astrocytes, and the choroid plexus and ependymal cells. In addition, we discovered using techniques of immunoelectron microscopy and biochemical purification of synaptic vesicles that ferroportin is associated with synaptic vesicles. In the blood-brain barrier, it is likely that ferroportin serves as a molecular transporter of iron on the abluminal membrane of polarized endothelial cells. The role of ferroportin in synaptic vesicles is unknown, but its presence at that site may prove to be of great importance in neuronal iron toxicity. The widespread representation of ferroportin at sites such as the blood-brain barrier and synaptic vesicles raises the possibility that trafficking of elemental iron may be instrumental in the distribution of iron in the central nervous system.[1]
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Postby orion98665 » Sat Mar 19, 2011 9:34 am

Bethr, I think you bring up some good points. What I find interesting
is that my brother who was dx with hemochromatosis after what was
first thought to be arthritis because both knuckles on his left hand
were severely inflamed. After further testing his dx was hemochromatosis.

What is even more rare is both my parents are carriers of the hemochromatosis gene. However, my wife is the one dx with ms. Nobody
on my side of the family has ms including all my relatives. It would
be interesting to know what my wife's iron levels are. Or if by chance she
is a carrier of the hemochromatosis gene. This will be my next step thru
blood test to determine.


Bob
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Postby Bethr » Sat Mar 19, 2011 1:48 pm

The good news, is there is so much research on iron metabolism, it's like the new frontier. The iron metabolism genes that are standing out in this abstract are not routinely tested for yet. They are thought to be rare.

I'm sure that the necessary gene tests will be available ASAP, another thing that needs to be pushed through.
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Gene mutation/haemachromotosis/MS

Postby Trent » Sun Mar 20, 2011 2:57 am

Hi,
I have PPMS, and a couple of years ago, whilst reading up on haemachromotosis, I realised that my (deceased) mother had been a sfere of this condition. She exhibited classic symptoms which were never picked up or acted on. She had arthritic knuckles, but no other arthritis. She kept a pan on the stove with paraffin wax to heat to relieve the pain. She had the typical bronzed skin, but didn't sunbathe (UK). She had had thyroid problems as an adolescent, and she died of a stroke at 68.
So, I told this to my GP who sent me for a bllood ferritin test and genetic testing. I was told my ferritin was high, though subsequent testing didn't uphold this. I had the gene mutation C282Y- one copy, which confirmed my mother's dx. My wife has haemachromatosis in her family with an uncle who died of it, so we have told our sons to get tested in case they have a copy from each of us - 1 in 4 ? But I havent been successful in getting blood drawn/phlebotomy. I go to Edinburg Clinic soon
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Postby Bethr » Sun Mar 20, 2011 7:48 am

Hi Trent, My mum had it too. Which is why all her children inherited one copy of C282Y. She had a great tan, even in the winter. We always wondered how she managed it, it made her look so healthy. She died suddenly of Ovarian Cancer at 53yrs. I've got the tan now too, but only on my lower forearms. It's fading since I got the iron lowered.

What they have found in the study is a high rate of other types of genetic hemochromatosis, with genetic mutations of other steps of iron metabolism. The ferroportin gene stands out to me because it's the opposite of classic hemochromatosis, it's the iron exporter (rather than importer), which in my mind would leave the iron deposited in tissue, unable to be removed easily back to plasma and building up each time the body decides to hide iron from a virus etc. Iron in the tissue, but low in the plasma, so would not show up on blood tests. These people would not tolerate phlebotomy.

I don't reckon I have that problem, or would I have improved so quickly when I reduced my iron overload?

I'm sure it won't be too long until they are testing these new hemochromatosis genes on people with MS and other diseases that accumulate iron in the brain and elsewhere, and treating accordingly.
But we still need to push this angle.
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Postby orion98665 » Sun Mar 20, 2011 8:17 am

Back when wife was first dx with ms and i was doing research i thought
paper was interesting.

http://fred.psu.edu/ds/retrieve/fred/investigator/jrc3
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Postby Brightspot » Sun Mar 20, 2011 2:26 pm

interesting read, thanks for the post
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Postby Bethr » Fri Apr 15, 2011 12:30 pm

Great bit of research on the tie in between the immune system and iron metabolism and movement across the BBB. This ties in well with the iron gene studies.

Altered Iron Metabolism Is Part of the Choroid Plexus Response to Peripheral Inflammation

Iron is essential for normal cellular homeostasis but in excess promotes free radical formation and is detrimental. Therefore, iron metabolism is tightly regulated. Here, we show that mechanisms regulating systemic iron metabolism may also control iron release into the brain at the blood-choroid plexus-cerebrospinal fluid (CSF) barrier. Intraperitoneal administration of lipopolysaccharide (LPS) in mice triggers a transient transcription of the gene encoding for hepcidin, a key regulator of iron homeostasis, in the choroid plexus, which correlated with increased detection of pro-hepcidin in the CSF. Similarly, the expression of several other iron-related genes is influenced in the choroid plexus by the inflammatory stimulus. Using primary cultures of rat choroid plexus epithelial cells, we show that this response is triggered not only directly by LPS but also by molecules whose expression increases in the blood in response to inflammation, such as IL-6. Intracellular conveyors of these signaling molecules include signal transducer and activator of transcription 3, which becomes phosphorylated, and SMAD family member 4, whose mRNA levels increase soon after LPS administration. This novel role for the choroid plexus-CSF barrier in regulating iron metabolism may be particularly relevant to restrict iron availability for microorganism growth, and in neurodegenerative diseases in which an inflammatory underlying component has been reported.


http://endo.endojournals.org/cgi/content/full/150/6/2822
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Postby 1eye » Sat Apr 16, 2011 8:11 am

Watched an interesting thingy on Darwinian genetics on (the dark) TV last night. It seemed to be saying that many developmental switches get turned off or on based not so much on what but on when things happen. So the reason I don't have gills, or do have funny valves or twisted jugulars has not so much to do with the fact that my mother smoked, but that she smoked exactly 3 minutes and 72277189206710 femtoseconds and no later or earlier, after I was conceived. Kismet, Hardy.

Put that in your Cray and smoke it :)
"Try - Just A Little Bit Harder" - Janis Joplin
CCSVI procedure Albany Aug 2010
'MS' is over - if you want it
Patients sans/without patience
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Postby Bethr » Sat Apr 16, 2011 1:41 pm

Hi 1eye, yes, it's fascinating. There are switches that turn on and off by the millisecond depending on what other switches are on or off. :?

This was mentioned in Genmati's Iron Gene Variants in MS study.
Getting my iron level lowered, gave me the same results as a successful CCSVI angioplasty treatment. Must have turned a switch off I think :idea: .
I know I have one HFE C282Y mutant switch on, that won't change (that's a fixed connection, no switch).
But that's not enough to cause the problems I've had. So I'm looking for another variant (with a fixed switch :lol: ).
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Re: Iron traffic gene variants in MS

Postby Bethr » Thu Dec 15, 2011 1:02 pm

More interesting research. I still think they will eventually find Ferroportin gene variants in MS.


The Journal of Neuroscience, 14 September 2011, 31(37): 13301-13311; doi: 10.1523/​JNEUROSCI.2838-11.2011
Iron Efflux from Oligodendrocytes Is Differentially Regulated in Gray and White MatterKatrin Schulz1, Chris D. Vulpe2, Leah Z. Harris3, and Samuel David1
+ Author Affiliations

1Center for Research in Neuroscience, The Research Institute of the McGill University Health Center, Montreal, Quebec H3G 1A4, Canada,
2Department of Nutritional Sciences and Toxicology, University of California, Berkeley, California 94720, and
3Department of Pediatrics, Vanderbilt University, Nashville, Tennessee 37232
Author contributions: K.S. and S.D. designed research; K.S. performed research; C.D.V. and L.Z.H. contributed unpublished reagents/analytic tools; K.S. and S.D. analyzed data; K.S. and S.D. wrote the paper.

Abstract
Accumulation of iron occurs in the CNS in several neurodegenerative diseases. Iron is essential for life but also has the ability to generate toxic free radicals if not properly handled. Iron homeostasis at the cellular level is therefore important to maintain proper cellular function, and its dysregulation can contribute to neurodegenerative diseases. Iron export, a key mechanism to maintain proper levels in cells, occurs via ferroportin, a ubiquitously expressed transmembrane protein that partners with a ferroxidase. A membrane-bound form of the ferroxidase ceruloplasmin is expressed by astrocytes in the CNS and regulates iron efflux. We now show that oligodendrocytes use another ferroxidase, called hephaestin, which was first identified in enterocytes in the gut. Mice with mutations in the hephaestin gene (sex-linked anemia mice) show iron accumulation in oligodendrocytes in the gray matter, but not in the white matter, and exhibit motor deficits. This was accompanied by a marked reduction in the levels of the paranodal proteins contactin-associated protein 1 (Caspr) and reticulon-4 (Nogo A). We show that the sparing of iron accumulation in white matter oligodendrocytes in sex-linked anemia mice is due to compensatory upregulation of ceruloplasmin in these cells. This was further confirmed in ceruloplasmin/hephaestin double-mutant mice, which show iron accumulation in both gray and white matter oligodendrocytes. These data indicate that gray and white matter oligodendrocytes can use different iron efflux mechanisms to maintain iron homeostasis. Dysregulation of such efflux mechanisms leads to iron accumulation in the CNS.

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