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MTHFR, Methylation and Metals: Dr. Amy A. Yasko
MTHFR, Methylation and Metals: Dr. Amy A. Yasko
MTHFR, Methylation and Metals: Dr. Amy A. Yasko
and Metals
Dr. Amy A. Yasko
Ph.D., ND, NHD, AMD, HHP, FAAIM
“What do schizophrenia, diabetes and autism have in
common? The answer is that many different factors act
together to influence their development. As well as
fundamentals like age and gender, other genetic and
environmental factors…may play a role in the onset of
these so-called multifactorial diseases.”
•Environmental
•Genetic
DISEASE
•Infectious
•Stress
Predisposing Factors That Increase
Susceptibility to Autism
H C
• T cells
• Intestinal mucosa
• Viral
lack of methylation
methylation and metals myelination
Melatonin
N-acetyl-5-methoxytryptamine
DNA Methylation
“DNA methylation may maintain the large amount of
non-coding DNA in an inert state.”
• To date, reelin and GAD67 mRNA and protein levels are reduced by approximately
50% in every cortical area, in hippocampi and in cerebella of postmortem brains
obtained from patients diagnosed with schizophrenia. In these same samples, there
were no changes in the levels of GAD65 immunoreactivity and mRNA that are
expressed in the same neurons that express reelin and GAD67. This suggests the
possibility that the genes encoding reelin and GAD67 may be coordinately regulated
and that there may be a defect in the regulation of the promoters of each gene that
compromises expression.
• Based on data obtained thus far, we suggest that methylation represents a switch
that can be used to turn off reelin expression under appropriate conditions. We are
addressing whether this may also be operative in the regulation of GAD67 and
GAD65. The role that methylation plays in regulating gene expression in the nervous
system is still under explored. We know that alterations in methylation can result in
mental retardation. Mutations that occur in methyl CpG binding proteins have drastic
consequences that occur postnatally.
The link between mental disorders and methylation aberrations
indicates that DNA methylation plays a vital role with regard to
normal functioning of the central nervous system (Robertson and
Wolffe, 2000 ). A further indication for an important role of
methylation in the brain is the observation of high levels of
neuronal methyltransferase (Goto et al., 1993 ). One of the first
mental disorders to be linked to errors in methylation was fragile-X
syndrome, a predominantly male form of mental retardation.
Patients with this disorder display an increase in methylation at the
CpG island upstream of the FMR1 (fragile-X mental retardation)
gene coupled with a decrease in FMR1 expression (Robertson
and Wolffe, 2000 ). An additional mental disorder linked to
alterations in methylation is Rett syndrome, an X-linked disorder
responsible for a predominantly female form of mental retardation.
This appears to stem from a mutation in the gene that encodes the
methylcytosine-binding protein MeCP2 (Nan et al., 1997 ).
Furthermore, Prader-Willi and Angelman syndromes, both
characterized by severe mental deficits, are linked to alterations
in the methylation patterns of a differentially methylated region
within the SNRPN promoter/exon1 region on the paternal and
maternal alleles, respectively (Shemer et al., 2000 ).
Beckwith-Wiedemann syndrome (BWS) is an example of a
developmental disorder due to alteration of methylation-
regulated imprinting mechanisms. BWS is characterized by
developmental growth disorders, which, in some cases, is
accompanied by increased expression of Igf2 (Issa and Baylin,
1996 ). Igf2 is typically a paternally expressed gene, but loss of
imprinting may be caused by abnormal patterns of methylation
(Maher and Reik, 2000 ). Furthermore, certain
methyltransferases may be essential in embryonic development;
a homozygous null mutation of de novo methyltransferase
Dnmt1 results in embryonic lethality in mice (Bestor, 2000 ).
Methylation-dependent T cell immunity to Mycobacterium
tuberculosis heparin-binding hemagglutinin.
Temmerman S, Pethe K, Parra M, Alonso S, Rouanet C, Pickett T, Drowart A, Debrie AS, Delogu G, Menozzi
FD, Sergheraert C, Brennan MJ, Mascart F, Locht C.
Nat Med. 2004 Sep;10(9):935-41. Epub 2004 Aug 08.
• In people with fragile X syndrome, the CpG island is methylated. As a result, the cell
is unable to copy the information in the FMR1 gene. Since an mRNA copy is not
made, FMRP will not be synthesized. Since there is no FMRP at the time and place
it is needed, the characteristics of fragile X syndrome are set in motion.
• Having more than 230 CGG repeats sets in motion methylation of part of the FMR1
gene. The methylation stops the synthesis of FMRP and the absence of FMRP
causes fragile X syndrome. We do not know why having too many CGG repeats
triggers methylation.
Fragile X
• DNA methylation
• FMRP is an RNA binding protein
• Excessive glutamate
• Decreased pruning
Friedrichs Ataxia
• DNA methylation
Reelin
• DNA methylation
• Decreased gaba
• Relationship to Schizophrenia
Reelin
• Methylation of the reelin gene is used to
regulate its activity.
• There are 100 potential sites for
methylation on the reelin gene.
• Lack of methylation may lead to the extra
long versions of the reelin protein found by
Kellers group.
Nucleic Acids Research July 2002, page 2930, PNAS March 29, 2000, page 3556
On the epigenetic regulation of the
human reelin promoter.
Chen Y, Sharma RP, Costa RH, Costa E, Grayson DR.
Nucleic Acids Res. 2002 Jul 1;30(13):2930-9.
NO MERCURY
DMSA Provoked Urine
July 16,2001
NO MERCURY
DMSA Provoked Urine
August 15, 2001
NO MERCURY
DMSA Provoked Urine
February 3, 2002
NO MERCURY
“ D-Glucaric Acid marginally
low: A result lower than normal
range may be of no clinical
significance, or reflect (1) an
environment unusually free of
xenobiotics…
TMG
B6
cysteine
S-adenosyl-methionine (SAM)
MW: 154.1
C7 H6 O2 S
9
PHIA
H-bond
H-bond (Flexible Calc. LogP
acceptors:
donors: 2 Bonds): (MDL QSAR): 2.21
2
1.99
Calc. LogP
Company:
(KowWin): 2.22
Anti-HIV Enzyme data: 0 TB Min MIC TB Min IC50
Lines of Data: 2 Lines of Data: 2
50 ug/mL
Number of References: 1
Number of References: 0
Number of References: 1 Lipinski: Y
Chemical Structure:
O-Mercaptobenzoic acid
Thimerosal
Requirement of RNA synthesis
for T Cell Activation
Thymidine=5 methyl uracil
Thimerosal
CO2Na
SHgCH2CH3 N
Thimerosal
CO2Na
S NH
N
Hg
N NH
“Viruses use a “Trojan horse” strategy in
which the victim assists the intruder. To
extract assistance from the host cell,
viruses use the detailed “inside
information” that they have acquired
during million of years of coevolution with
their hosts.”
Kalpana Ghoshal,1 Sarmila Majumder,1 Qin Zhu,1 John Hunzeker,2 Jharna Datta,1
Manisha Shah,3 John F. Sheridan,2 and Samson T. Jacob1
Copyright © 2001, American Society for Microbiology
Mol Cell Biol. 2001 December; 21 (24): 8301–8317
DOI: 10.1128/MCB.21.24.8301-8317.2001
• Aluminum Alzheimers
• Organophosphates Parkinson’s
• Pyridostigmine ALS/Gulf War
Syndrome
• Aluminum Autism
Tetanus Toxin
Acetylcholinesterase Inhibition
• Pinpoint pupils
• Blurred vision • Muscle twitching
• Hypersecretion • Muscle weakness
• Bladder incontinence • Dilated pupils
The Autonomic Nervous System
Structure Sympathetic Stimulation Parasympathetic Stimulation
Iris (eye muscle) Pupil dilation Pupil constriction
Salivary Glands Saliva production reduced Saliva production increased
Oral/Nasal Mucus production
Mucus production increased
Mucosa reduced
Heart rate and force
Heart Heart rate and force decreased
increased
Lung Bronchial muscle relaxed Bronchial muscle contracted
Gastric juice secreted; motility
Stomach Peristalsis reduced
increased
Small Intestine Motility reduced Digestion increased
Large Intestine Motility reduced Secretions and motility increased
Increased conversion of
Liver
glycogen to glucose
Kidney Decreased urine secretion Increased urine secretion
Norepinephrine and
Adrenal medulla
epinephrine secreted
Wall relaxed Wall contracted
Bladder
Sphincter closed Sphincter relaxed
Considerations
• Use of choline, lecithin, phosphatidyl choline
• Seizure activity and choline
• Organophosphates (pesticides), GMO
• Endosulphan pesticides (nuts) and gaba
release
Aluminum leads to stimulation of
the immune system
Dietary nickel and folic acid interact to affect folate and methionine metabolism in the rat.
Uthus EO, Poellot RA.
United States Department of Agriculture, Agricultural Research Service, Grand Forks Human Nutrition Research Center, ND
58202-9034, USA.
… Because of this, it is proposed that the physiological function of nickel is related to the
common metabolism shared by SAM and FIGLU. Possibly the physiological function of
nickel could be related to the tissue
concentration of 5-methyltetrahydrofolate (MTHF)
or tetrahydrofolate (THF).
Valproic acid can be used to treat seizures.
• Malic acid
• EDTA
Step 2 for
Metals
T Aluminum (ug/g Creatinine)
h
e
E200 180
f
f150
e
c
120
t100
o 50
f 35
19 20
M 0 0 0 0
e
6/18/03 7/10/03 7/24/03 8/5/03
6/17/03 7/3/03 7/17/03 8/1/03
t
a Safe Range: 60
l
R
N
Mercury (ug/g Creatinine)
24
25
20
15
15
12
10 9.8
10
7.1
6.4 6.5 6.6
5.4 5.3
5
3.9
2.8
2.3 2.3
1.8
0 0
0
7/10/03 8/15/03 10/1/03
6/17/03 8/1/03 9/3/03
Safe Range: 5
Lead (ug/g Creatinine)
20
18
15
13
10
7.4
6.6
5.7
5
3.6
3.3
2.3
1.7
0.8 0.8 1 1 1 1.1
0.4 0.2 0.6 0.6 0.4
0.2 0 0
0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
Safe Range: 5
Tungsten (ug/g Creatinine)
12 12
10
8.8
6.1
6 5.7
5.4
2 1.6
1.4
1
0.8 0.8 0.8
0.5 0.6
0.4 0.4 0.3 0.3 0.3 0.3 0.3
0.2 0.2
0 0 0 0 0 0 0 0 0
Creatinine
200 200
170 170
150
100 90 92
83
76
66
61
57
50 45
40
50 53
35
30
24 25 22 26
18
0
3/30/044/9/044/17/046/17/046/21/047/20/048/25/049/8/049/23/0410/7/04
3/23/044/5/044/12/046/1/046/20/047/12/048/4/048/30/049/13/049/29/0410/12/04
6 5.9
3 2.7
2.5
2.2
2 1.9
1.5 1.5
1 0.70.7
0.3
0 0 0 0 0 0 0 0 0 0 0 0
3/30/044/9/044/17/046/17/046/21/047/20/048/25/049/8/049/23/0410/7/04
3/23/044/5/044/12/046/1/046/20/047/12/048/4/048/30/049/13/049/29/04
10/12/04
Step 3 and
Beyond