1. Patients launch $1.27 million crowdfunding campaign for ME/CFS gut microbiome study.
    Check out the website, Facebook and Twitter. Join in donate and spread the word!
ME/CFS: A disease at war with itself
We can all agree that ME/CFS is a nasty disease, particularly in its severe form, but there are abundant nasty diseases in the world. What is unique and particularly confounding about our disease is that so much controversy surrounds it, and not only surrounds it, but invades it too.
Discuss the article on the Forums.

Slc1A1 gene, cysteine and glutamate tranport

Discussion in 'Detox: Methylation; B12; Glutathione; Chelation' started by pgoody, Jun 1, 2013.

  1. pgoody

    pgoody

    Messages:
    66
    Likes:
    33
    I recently started looking in the Slc1a1 gene because of it is highly implicated in OCD. Several other genes are implicated as well, in regards to serotonin and dopamine, but from what I have been reading from Yale's research and pubmed, excess glutamate in the cerebral cortex and in various brain process (especially in the frontal cortex) is seen as being a possibly physiological cause of OCD. I have also read that SSRIs' primary mechanism (in treating OCD) might be in its ability to correct the glutamate balance as increased serotonin modulates glutamate.

    Slc1a1 is a gene that encodes for the EAAC1 enzyme which is responsible for transport of glutamate from the kidneys and from interneuronal synapses in the brain. People with dysfunction in this gene may have the inability to transport glutamate out of the synapses (and dysfunctional kidneys, the physiology I don't understand exactly), which leads to higher levels sitting around leading to hyperglutamatergic conditions. People who have issues with this gene can have defects that result in high levels of glutamate and aspartate in a amino acid urine analysis, and it's possible that for some individuals with OCD that high levels of both in the test may be an indicator of a bad Slc1a1 gene. People with high urine counts of these substances would be considered to have Dicarboxylic Aciduria (Where I found out about the test: http://phys.org/news/2011-01-obsessive-compulsive-disorder-ocd.htmlI) found a great article that discusses this and the genetic region of Slc1a1 that is implicated.

    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3007158/

    Then on the bottom part of the article, it starts talking about how cysteine is and glutathione are also affected by this defective gene. Here is some of the meat of the aricle:

    "The increased affinity for l-cysteine resulting from the R445W mutation in SLC1A1 led to a reduction in l-cysteine uptake to levels that were 2% of those of WT, while I395del prevented l-cysteine uptake by SLC1A1. Consequently, the increase in l-glutamate and l-cysteine affinity for R445W not only reduced the size of the transporter currents observed but also substantially reduced the rate of substrate transport."
    [...]
    “Our findings on SLC1A1 disruption in humans were in agreement with the DA phenotype reported in Slc1a1 nullizygous mice. Despite this phenotypic similarity between species, the appearance of age-related neurodegeneration, which was observed in outbred Slc1a1 nullizygous mice, has not yet been clearly documented in humans. This neurodegeneration was attributed to decreased neuronal cysteine uptake. Cysteine is the rate-limiting substrate for the synthesis of glutathione, and neurons are dependent on the extracellular uptake of cysteine for normal function. Most cell types transport cysteine in the form of cystine, by heteroexchange with glutamate via the sodium-independent system x, but in vitro studies suggest that neurons lose this capacity as they mature. Neurons use sodium-dependent cysteine uptake as the major route for cysteine uptake (80%–90% of total uptake), most of which is handled by SLC1A1 (75%–85% of total sodium-dependent uptake). Thus, abrogation of cysteine uptake in the neurons of outbredSlc1a1 nullizygous mice led to impaired glutathione metabolism, increased oxidative stress, and neuronal death"

    This might be an underlying reason for why people with OCD benefit from NAC, if they have some inability to transport the cysteine. If you read the whole article however, there are a whole slew of SNPs that could potentially alter enzyme function, while this article focuses primarily on two specific regions of Slc1A1.

    Edit**
    I found out why NAC helps people with ocd and how it modulates glutamate in this article.
    http://www.ocd.yale.edu/researchers/329_114509_Pittenger et al (2011) Glutamate abnormalities in OCD.pdf

    "Indeed, excess glutamate has long been known to lead to neuronal death, a phenomenon known as excitotoxicity (Olney, 1969). Glutamate concentration is therefore tightly regulated. The principal mode of regulation is through high-affinity glutamate transporters, which efficiently remove glutamate from the perisynaptic and extrasynaptic spaces (Danbolt, 2001). Quantitatively, glutamate transporters on glial cells – principally astrocytes – are responsible for the majority of glutamate removal; these astrocytic glutamate transporters are a target of the glutamate-modulating drug riluzole, which has shown promise in the treatment of refractory OCD (Pittenger et al., 2008a). A smaller fraction of glutamate is removed by the neuronal glutamate transporter, EAAC1/EAAT3; as reviewed below, polymorphisms in the gene encoding this transporter have been repeatedly associated with OCD in recent studies (Arnold et al.,2006; Dickel et al., 2006; Stewart et al., 2007; Shugart et al., 2009). Finally, glutamate is also transported into glial cells in exchange for the oxidized amino acid cystine via the glutamate-cystine antiporter; undersome circumstances the activity of this antiporter, which is influenced by the drug N-acetylcysteine, may be the principal determinant of baseline levels of extrasynaptic glutamate (Kalivas, 2009)"
    Valentijn, Jarod and alex3619 like this.
  2. Lotus97

    Lotus97 Senior Member

    Messages:
    2,015
    Likes:
    419
    United States
    Is this gene tested with 23andMe?
  3. pgoody

    pgoody

    Messages:
    66
    Likes:
    33
    There are a lot of SNPs along the Slc1A1 gene. If you look in the article it talks about the 49 or something kb length of gene that is affiliated with OCD and in that region alone there are tons of SNPs, certain ones which have been studied for gene dysfunction and OCD. Certain ones are for sure, such as rs301434 and rs3087879, which I had read about in relation to OCD in other studies. Here's the image that refers to the different SNPs, run them through your 23andMe raw data and see what comes up. I'll have to look through this article again, I just read through it once. I was trying to find out if 23andMe would be able to tell you if you had this C1333T allele or the deletion, but I couldn't find out how to search for them as they did not appear to have a searchable rs number.

    Attached Files:

  4. Valentijn

    Valentijn Activity Level: 3

    Messages:
    6,262
    Likes:
    8,935
    Amersfoort, Netherlands
    SLC1A1 is on chromosome 9 from location 4490427 to 4587469.

    23andME (according to their sample report), test the following locations in that range (red ones have easy-to-find research attached to them in obvious places):

    rs972519
    rs7045401
    rs10814991
    rs7021409
    rs10974577
    rs7860087
    rs7023050
    rs10758624
    rs10814995
    rs10491732
    rs13289148
    rs16921385
    rs10974584
    rs2094806
    rs2150195
    rs7041093
    rs1980943
    rs1888279
    rs10974587
    rs12351328
    rs10814998
    rs17755777
    rs10115600
    rs10116014
    rs10974591
    rs10815002
    rs7864309
    rs4742004
    rs10815004
    rs6476874
    rs7849913
    rs17756150
    rs10758629
    rs6476875
    rs7848533
    rs10974611
    rs10974615
    rs10491731
    rs928209
    rs10815016
    rs10758631
    rs10815017
    rs10815018
    rs10815019
    rs10739065
    rs2039290
    rs7856675
    rs3780415
    rs10974619
    rs3780414
    rs4742006
    rs4742007
    rs7858877
    rs10974624
    rs9407286
    rs10974625
    rs4742009
    rs6476878
    rs2228622 (G is normal, AA is somewhat uncommon)
    rs7022772
    rs11792309
    rs3780413 (Not much info)
    rs7864496 (C is normal, TT is somewhat uncommon)
    rs3780412 (All variations pretty common)
    rs12682807(A is normal, CC is VERY uncommon)
    rs2072657 (T is normal, GG is pretty uncommon)
    rs301430 (All variations pretty common)
    rs1471786
    rs301431
    rs159914
    rs6476879
    rs188537
    rs301433
    rs4742011
    rs301434 (All variations pretty common)
    rs3087879 (G is normal, CC is pretty uncommon)

    In most cases it looks like a combination of the "wrong" genes is needed to have even a minor association with OCD, such as rs2228622 (A) rs3780413 (C) AND rs3780412 (G) at http://archpsyc.jamanetwork.com/article.aspx?articleid=210424.
    pgoody likes this.
  5. pgoody

    pgoody

    Messages:
    66
    Likes:
    33
    I think you're right it takes a combination of the wrong genes, and that possibly includes many other factors other than Slc1A1. There are a LOT of articles on pubmed about various slc1a1 genes in relation to OCD, and that's because I guess there are many regions of the overall gene that can effect enzyme activity, kind of like there are many polymorphisms in COMT that effect its ability to reduce catecholamines. In the case of OCD, and many other conditions I would like to say, it's probably impossible to point at one gene and say "here is my problem". Instead it's more like "here's part of my problem".

    I've read that OCD might be caused by an imbalance (low) of serotonin as a result of imbalance autoimmune function, http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3626880/. Another article down that alley: (http://pubs.acs.org/doi/pdf/10.1021/cn300186b) I've read that it can be the cause of an autoimmune disease (I guess this is where PANDAS fits in) where certain bacteria such as streptoccocus pyrogenes causes the body to produce antibodies that attack if I remember correct, the basal ganglia as they mistake it for the strep bacteria. I've read that in OCD there can be problems with excessive dopamine and glutamate, in various regions of the brain. ( http://mybrainnotes.com/ocd-dopamine-basal-ganglia.html). COMT activity is also implicated. I am met/met for, and OCD is affiliated with high prefrontal cortex activity, including glutamate as well. Here is another article where dopamine receptor genes are implicated: http://www.ncbi.nlm.nih.gov/pubmed/23127570)

    Here is a more comprehensive meta-analysis of OCD. It compiles genes from many studies in regards to OCD and lumps them into one study. I currently don't have access to it, but I will have the full article within the week if anyone is interested, but here is the summary: (http://www.ncbi.nlm.nih.gov/pubmed/22665263).

    Here are the current medications going under clinical trials for OCD: http://clinicaltrials.gov/ct2/results?cond="Obsessive-Compulsive Disorder". You will notice that the list includes antioxidant NAC, antiglutamate memantine and riluzole (see article below), probiotics such as cycloserine, anti NMDA glutamate receptor ketamine aka anesthetic (which I would never use as treatment for my OCD).

    Here's a recent study concerning OCD and the Slc1a1 gene: (http://www.ncbi.nlm.nih.gov/pubmed/23606572).

    Here are a few studies about Serotonin 1b receptors in relations to OCD:
    http://www.ncbi.nlm.nih.gov/pubmed/21920503
    http://www.ncbi.nlm.nih.gov/pubmed/23377022

    Here is a study about the effectiveness of an anti-glutmatergic medication called Riluzole in treatment of OCD:
    http://medicine.yale.edu/psychiatry/ocd/research/40056_2005 Coric et al Biol Psych.pdf

    My hope is that in the next half century that the medical community will be able to "pinpoint" regions of genes that are associated with OCD and will be able to treat patients more specifically to their root problem. It has sort of been my goal to look through some of these studies and compile a list of genes significantly correlated with OCD.
    Valentijn likes this.
  6. pgoody

    pgoody

    Messages:
    66
    Likes:
    33
    Here is an interview with Dr. Pittenger, who I believe is one of the lead scientists at the OCD research center at the Yale School of Medicine. The interview begins around 1:30, and he starts really getting into the Slc1A1 gene at about 10 minutes in: ()

    Here is a link to the OCD International Foundation, of which Pittenger is a part of. This provides an overall description of current OCD theories. http://www.ocfoundation.org/glutamate.aspx
  7. xjhuez

    xjhuez Senior Member

    Messages:
    170
    Likes:
    39
    Interesting info, thanks for sharing. I intend to dig into these links when I have some free time.

    Anecdotal, but I took NAC for about a year and it did lessen my OCD symptoms.
  8. roxie60

    roxie60 Senior Member

    Messages:
    1,672
    Likes:
    523
    Central Illinois, USA
    I thot A=T was always abnormal alelles and C=G were always normal alelles - this stuff is so confusing. Also rs3780412 you show (G) as abnormal but my 23andMe results show CT. I wonder if it has to do with the + vs _ stand they use?
  9. pgoody

    pgoody

    Messages:
    66
    Likes:
    33
    Roxie,

    The idea that certain alleles within genes are "mutations" may be misleading. While certainly your genome may contain some rare "defects" (such as rare allele configurations and deletions) many of the minor alleles that are considered mutations in Yasko's literature are not exactly mutations but rarer versions. In fact, it isn't always the rarer allele that will result in poorer health, some of the most common alleles, or wildtypes (WTs) can promote certain dysfunctions. It all depends on what gene your looking at and what condition you are trying to determine you have. For example, according to Yasko I am (AA,+/+) for COMT Val158Met, rs4680, but according to dbSNP there is a nearly 40% chance of having one A allele, and then a roughtly 16% chance of having the AA "mutation", which in my opinion isn't all that rare. Within certain genes having the major allele may mean you have more risk of, in this case, OCD. I think that the allele's designated by Valentijn's post as "uncommon" does not necessarily determine which of these alleles make you more likely to have OCD. If you do a promethease analysis of your DNA you will see in some cases, that the major homozygotes, which over 60 percent of people have my contribute to certain disease, which yes makes things all the more complicated. However there are certain genes where the mutations can have a real significant impact on your health, and I think Yasko's material has cherry picked a bunch of those all within one region (MTHFR, CBS, COMT).

    And sorry if my response was misdirected, as I just read your comment again and felt like I didn't actually answer your question. :whistle:
    roxie60 and Valentijn like this.
  10. Valentijn

    Valentijn Activity Level: 3

    Messages:
    6,262
    Likes:
    8,935
    Amersfoort, Netherlands
    The concept of "normal" is over-simplistic, and many of the alleles indicating a statistically significant risk for a disease (especially when combinations of specific SNPs with specific alleles are needed) are quite common.

    What they have instead of "normal" is the "major" or "ancestral" allele. But again, this usually doesn't mean much. It just indicates which variant is more common or has a more established historical existence. Each SNP has two alleles associated with them. One SNP might have a major allele of A and a minor allele of G. And another SNP might have the opposite. Or a major allele of C and a minor allele of A.

    For rs3780412 I didn't say G is abnormal, I said "rs3780412 (All variations pretty common)", and it's associated with OCD to some (probably statistically significant yet quite small) extent when combined with specific versions of two other SNPs. But there are some instances where the research is a bit muddled, and it seems an though at some point people were looking at A/G for an SNP when everyone else was looking at T/C for the same SNP. I'm not sure how or why this happens, but http://www.ncbi.nlm.nih.gov/projects/SNP/ seems to have the updated and authoritative versions.

    The NCBI and the study linked above both say A/G, so I don't know where 23andMe is getting C/T from. +/- are just symbols which geneticgenie or whatever throws in to make the chart seem easy to interpret. The +/- don't come from 23andMe at all ... their entire entry for the SNP looks like: "rs3780412 9 4572480 CT".
  11. roxie60

    roxie60 Senior Member

    Messages:
    1,672
    Likes:
    523
    Central Illinois, USA
    You are right you did not say abnormal, I interpreted this as meaning abnormal, my bad,sorry:

    In most cases it looks like a combination of the "wrong" genes is needed to have even a minor association with OCD, such as rs2228622 (A) rs3780413 (C) AND rs3780412 (G) at http://archpsyc.jamanetwork.com/article.aspx?articleid=210424.
  12. pgoody

    pgoody

    Messages:
    66
    Likes:
    33
    If you by chance want to involve yourself in the complexities that underlie the functions of one enzyme, read this:
    http://www.readcube.com/articles/10.1038/tp.2013.35. More info on the SlC1A1 and OCD.

    The SNPs that displayed the most reproducible associations with OCD, schizophrenia and autism are located toward the 30 portion of the EAAC1 gene, and include rs2228622 (located in exo 4, near the internal promoter, P2), and rs301979 and rs30143420 (located near exon 11), and rs3087879 (located in exon12), suggesting the possible involvement of the P2 transcript and/or ex11skip in psychiatric disorders.

See more popular forum discussions.

Share This Page