1. Justin Durland
Honors Contract Research Report
12/1/14
Identifying Suspected Modifier Genes in Huntington’s Disease in Hope to Reduce Disease
Pathogenesis
The human body is a sophisticated system that requires the conjoined effort of multiple
proteins to function properly and effectively. Protein formation is an extremely efficient process,
but can sometimes go wrong due to mutations in a gene. Proteins that fail to fold into their
appropriate structure are commonly destroyed through degradation processes. However, this is
not always the case when there is a defect in an individual’s genome that codes for an active
mutant protein. There are several human diseases that are caused by a mutation in a single gene.
Huntington’s chorea, a fatal and incurable disorder, is such a disease that results from a mutant
gene coding for a gain-of-function protein that has destructive effects in the body, specifically in
neuron cells. The foundation to the pathogenesis of Huntington’s disease is from the mutant
huntingtin protein interfering with normal cell functions, ultimately causing the death of neurons.
In human genetics, it has been observed that separate independent genes and their gene products
can influence the extent of an effect another gene has. These genes with modifying effects have
been seen to have both beneficial and harmful effects on the pathogenesis of disease, such that
years of life can potentially be gained or lost in affected individuals. Modifiers have become
progressively more acknowledged as important sources of phenotypic variation, and are thought
to partly explain the relationship of unexpected phenotype of a known genotype [1]. For this
reason, identifying and targeting modifier genes through enhancement and suppression strategies
may one day be a powerful method in modulating Huntington’s disease pathogenesis. In this
paper I explore the foundations of Huntington’s disease, ways to target possible genetic

2. modifiers associated with the disease, and evidence in which Huntington’s disease pathogenesis
is proposed to be modified by specific mismatch repair genes and a co-activator gene called
PPARGC1a. This is all in hope to strengthen the prospect of finding therapeutic methods in
utilizing modifiers and reducing the destructive path of Huntington’s disease.
A protein’s final three-dimensional structure is based on the amino acid interactions
within it. These interactions are extremely important for that protein to interact and function the
way it should throughout the body. Individuals that are unaffected by disease have the necessary
cellular and protein interactions needed to carry out normal organismal function [2]. To
demonstrate the necessity of proteins interacting in their native form, we can look to
Huntington’s disease which results from duplicative repeats within the wild type protein. These
repeats interact with the mutant huntingtin and other proteins in a way that is harmful to cells.
When the repeats are extended to a certain point, there is chemical favorability in the formation
of protein aggregates [3]. Aggregate accumulations within neurons are toxic to the cells and
disrupt a multitude of cellular processes. This disruption of cell function ultimately leads to cell
death and the onset of disease symptoms [4].
Huntington’s disease is characterized by abnormal involuntary movements, cognitive
decline, and psychiatric disturbances. These symptoms are primarily through the loss of striatal
neurons in the brain. Huntington’s disease origin was traced to the short arm of chromosome 4 in
exon 1 through genetic linkage of DNA sequence markers and DNA cloning and sequencing
techniques. Using these strategies and subsequently monitoring disease onset, researchers found
that the CAG trinucleotide repeat of the huntingtin gene is the pathogenic origin of the disease.
Thus, the mutation seen within individuals diagnosed with Huntington’s disease is an extensive
duplication of this CAG trinucleotide repeat. The huntingtin protein encoded by the huntingtin

3. gene is expressed around the body, but largely in neuronal and peripheral tissues [5].
Interestingly enough, the function of the normal huntingtin protein without the extended CAG
repeat is not fully understood. However, huntingtin’s expression is essential to human
development [6]. The normal number of CAG repeats seen within the gene is said to be less than
36. Repeat numbers that exceed this are generally associated with disease onset. This elongated
CAG repeat creates an unstable poly-glutamine tract in the huntingtin protein that appears to
mediate a dominant gain-of-function, resulting in aggregations and dysfunction of a range of
cellular processes [7]. Hence, the extended length of the CAG tract is linked to disease
pathogenesis and symptom onset. The discrepancy in CAG repeat and symptoms are heritable.
Nevertheless, there are considerable variances of disease age of onset that is not fully explained
by CAG repeat length. The existence of these variances highlights the possibility of modifier
gene influences on the disease course. The strategy in recognizing modifier genes associated
with Huntington’s disease has been by observing different cellular pathways that are linked to
disease symptoms [8]. A modern approach has been by running bioinformatics and statistical
analyses of databases full of suspected Huntington’s disease modifiers. This bioinformatics
approach reduced over 800 suspected modifier genes to 24 ‘novel candidates’. In combination
with previous data, the probability of finding a realistic modifier target for therapeutic
intervention of Huntington’s disease has greatly increased [9].
Modifier genes can be difficult to identify. This is because environmental factors, along
with all of our body’s different gene products together, often result in variable phenotypes. Since
such factors can cause a trait to be expressed in one setting and not expressed in another,
distinguishing modifier genes is best accomplished through observing genetically identical
individuals in similar environments or by conducting tests on knock-in/knock-out mice in

4. controlled environments. Mice are not fully relevant to humans, but they can provide powerful
information on a location and function of homologous genes in humans, without crossing human
ethic boundaries. Therefore, mice studies allow scientist to conduct more purposeful and
educated research into a gene’s involvement in human disease. By using identical environments,
individuals and mice studies, uncontrolled variables and biases are minimized as best as possible.
In this way, modifier connections can be made in such things as dominance, penetrance,
expressivity, and age of onset of a disease [10].
Being that there are still numerous mysteries to Huntington’s disease, further research
must be conducted for confirmation of specific modifier influences. However, simple
observational studies on individuals affected by Huntington’s disease provide evidence for
modifier genes influencing the onset and penetrance of the disease. An instance of modifiers
affecting penetrance can be seen in individuals with 37-39 CAG repeat range, an intermediate
but technically termed ‘affected’ repeat range of Huntington’s disease. In this range it is
observed that some Huntington’s individuals are clinically affected by the mutant huntingtin
protein, while others are not. Those who are not affected by mutant huntingtin show no
expression of disease symptoms and survive unaffected into their elderly years [11]. Clearly
there are genetic influences distinguishing whether or not Huntington’s symptoms are expressed
in this instance. However, there has been no distinct gene influence found, so there can be no
conclusion to say this observed incomplete penetrance of Huntington’s disease is due to specific
modifier genes. Therefore, modifier genes affecting the onset of Huntington’s disease are most
significant for further discussion.
Huntington’s onset can vary from childhood to late adulthood, or not at all, with the most
recognized cause due to a CAG trinucleotide repeat greater than 40 in the huntingtin gene. The

5. rate of huntingtin CAG repeat expansion varies in different individuals, along with the onset of
disease symptoms in individuals with a similar number of repeat sequences. Research shows
promising data in modifiers affecting these aspects of Huntington’s pathogenesis. A recent
hypothesis led researchers to the effect of mismatch repair proteins, MSH2/MSH3 and
MLH1/MLH3, in Huntington’s affected individuals. Due to occasional sequence slip-outs
experienced within the length of the mutant huntingtin gene’s CAG repeat, these mismatch repair
proteins appear to act on the slip-out event in a way that ultimately increases the expansion
efficiency of the CAG repeat. Hence, the mismatch repair proteins contribute to lowering the age
of onset of the disease [12]. Additionally, Huntington’s symptoms have been related to
mitochondrial dysfunction. This dysfunction commonly results in neuron death due to oxidative
stress. Many studies have drawn attention to a mitochondrial regulator gene called PPARGC1a
which shows beneficial modulation of mitochondrial dysfunction symptoms, when up-regulated,
through promoting proper mitochondrial regulation and antioxidant pathways [13]. Together, the
examples above help support the idea that genetic modifiers could be important in varying the
extent of Huntington’s pathogenesis.
Since the huntingtin gene CAG repeat corresponds to the pathogenic progress of
Huntington’s disease, there is fundamental reason to target genes that may be associated in
modifying the somatic expansion of the CAG over time. Replication slippage is believed to be a
key mechanism for generating the CAG expansions in the mutant huntingtin gene. Slippage
resulting during replication by DNA polymerase is thought to be a cause of sequence instability
between CAG/CTG in the huntingtin gene. This instability sometimes results in a single stranded
DNA slip-out and loop structure in the DNA strand. The loop permits displacement between
sequence triplets, and in the presence of DNA polymerase, additional triplets can be replicated

6. within the gene [14]. Since it is impractical to therapeutically target such an important protein as
DNA polymerase, separate modifiers in somatic expansion have been sought. Studies found that
CAG/CTG sequence instability also results in somatic expansion through DNA mismatch
recognition processes. There is particular association with DNA mismatch recognition proteins
MSH2/MSH3 and DNA mismatch repair proteins MLH1/MLH3 that show intriguing effects on
CAG expansion [12].
Do to the sensitivity of influencing human genes encoding mismatch repair proteins,
most studies have been done on human homologue genes found in Huntington’s disease knock-
in/knock-out mice. Candidate gene knock-out approaches found MSH2 and MSH3 genes,
encoding mismatch recognition complex proteins that interact with one another, were necessary
for CAG expansion in homolog strains of Huntington’s disease mice [15]. The MSH2 protein is
linked to contribute to striatal repeat instability, while the MSH3 protein being necessary to CAG
expansion [16]. A study specifically focusing on two dissimilar strains of the MSH3 gene in
Huntington’s disease mice revealed that different coding regions within the two MSH3
transcripts resulted in significantly different MSH3 protein levels. The mouse strain that had less
overall MSH3 protein concentrations had a decreased CAG expansion rate, while the mouse
strain with greater MSH3 protein concentrations experienced an increased expansion rate. The
data on these two mice strains suggests that polymorphisms within the coding region of the
MSH3 gene are modifying CAG expansion relative to the stability of the final MSH3 protein
[17]. Similar studies later suggested that associated mismatch repair genes MLH1 and MLH3
played just as significant, if not more, of a role in somatic expansion as MSH2/MSH3. The
MLH1/MLH3 genes encode mismatch repair proteins that interact with MSH2/MSH3 mismatch
recognition proteins. Together with other proteins, a mismatch repair complex forms. Studying

7. MLH1/MLH3 null background Huntington’s mice versus those with the genes revealed a
significant decrease in somatic expansion of the CAG repeat in the null background compared to
the wild type expression. A separate but related study on dissimilar levels of both MLH1 mRNA
and MLH1 proteins within different strains of Huntington’s mice showed somatic expansion was
most efficient in striatal cells when higher levels of MLH1 proteins were present. Studying the
MLH1 gene locus of these different mice strains showed high polymorphisms within the MLH1
gene. This gives support to the hypothesis that genetic variations in the MLH1 gene may underlie
MLH1’s modified expression, and thus, its effect on somatic expansion of the mutant huntingtin
gene. Together, the evidence suggests that the mismatch repair genes MSH2/MSH3 and
MLH1/MLH3 have a role as modifiers in the somatic expansion of the mutant huntingtin gene.
Recent data also provides insight on the presence of gene variations, specifically within MSH3
and MLH1 gene loci, that underlie the mismatch repair gene’s level of influence on expansion.
The fact mismatch repair proteins repair errors in DNA replication tells us the DNA
mismatch repair complex, in the case of the mutant huntingtin gene, must somehow affect the
addition of a CAG repeat. A clear mechanism in which the mismatch repair proteins influence
somatic expansion is uncertain. The data shows that the CAG/CTG repeat instability is initially
recognized by MSH2/MSH3 mismatch recognition proteins. MLH1 and MLH3 are subsequently
recruited to contribute to a mismatch repair complex. The complex, likely coupled with other cell
processes or perhaps even DNA replication, processes the CAG repeats in a way that an
expansion results. Interestingly, the mismatch repair proteins may then be responsible for both
influencing expansion in addition to enhancing the chances of further expansion events. This is
because the greater the amount of CAG repeats within the huntingtin gene, the greater the
likelihood of sequence instability that will be recognized and processed by the mismatch repair

8. proteins [12]. MSH2/MSH3 and MLH1/MLH3 mismatch repair proteins show evidence in
modifying the huntingtin gene CAG repeat. Hence, there is reason for further investigation in
their influences to provide targets for therapeutic intervention.
Separate from CAG trinucleotide somatic expansion, there is considerable evidence
suggesting mitochondrial dysfunction in the neurons of Huntington’s affected individuals. This
evidence includes reduced oxidative phosphorylation, abnormal mitochondrial membrane
permeability, and oxidative stress, among others. Correspondingly, Huntington’s knock-in mice
experience severe mitochondrial respiration deficiency and ATP production shortage in striatal
cells [13]. One of the most prominent impacts of mitochondrial dysfunction is subsequent neuron
death due to oxidative stress. Mitochondria are the source of at least 80% of the reactive oxygen
species in our body. Stress and toxins in neuron cells that block proper mitochondrial function
can result in a flux of free radicals that cause cell damage and death [18]. There are a couple
hypotheses by which the mutant huntingtin protein is proposed to cause mitochondrial
dysfunction in such a way. For starters, the huntingtin protein’s poly-glutamine tract has been
suggested to directly interact with mitochondria, either acting as an external uncoupling agent to
ATPase or a toxin to the mitochondria. The poly-glutamine’s interactions are thought to act in a
way that depolarizes the mitochondrial membrane and/or increases its permeability. Ultimately,
the interaction of the mutant huntingtin protein with the mitochondria increases the presence of
oxy-radicals, causing cellular oxidative stress, and result in cell death [19]. Another suggested
influence of the mutant huntingtin protein is through it affecting the expression of transcription
factors involved in regulating mitochondrial genes. The specific genes suggested to be affected
by mutant huntingtin regulate mitochondria function and oxidative stress, therefore also
associating mutant huntingtin with oxidative stress and cell death. The mutant huntingtin protein

9. influence on mitochondrial dysfunction provides a foundation for searching for modifier genes
that can counteract Huntington’s suggested oxidative and inhibiting effects [20].
Certain mitochondrial regulator genes are being extensively studied for having potential
in being modifiers of Huntington’s pathogenesis. One of importance called PPARGC1a, which
encodes the co-activator protein PGC-1a, has shown to provide general beneficial influence on
regulating mitochondrial biogenesis, oxidative phosphorylation activity, and antioxidant defense
[13]. The known influence of PGC-1a led scientists to explore a correlation between it and
Huntington’s disease. Research found that different variations of PGC-1a levels were related to
the severity of Huntington’s disease pathogenesis, where higher levels of PGC-1a corresponded
to later disease onset and vice versa. PGC-1a’s expression appears to be negatively affected by
the mutant huntingtin protein. It is suggested that PGC-1a’s expression is in some way inhibited
by, or that the PGC-1a protein directly interacts with, the mutant huntingtin protein. In so doing,
PGC-1a does not perform its normal function in maintaining proper mitochondrial regulation in
Huntington’s individuals [21]. Studies on mice models show PGC-1a mRNA and protein levels
are significantly decreased in Huntington knock-in mice. Also, it is observed that there are
increased pathogenic rates of neurodegeneration of striatal neurons when PGC-1a knock-out
mice are crossed with Huntington’s disease knock-in mice. This evidence both supports the
claim that the mutant huntingtin protein in some way represses PGC-1a, and that PGC-1a
repression is linked to earlier disease onset [22].
There is evidence of gene sequence variants associated with varied PGC-1a expression.
Data of PGC-1a modifying influence has been linked to two independent single nucleotide
polymorphisms located in the PPARGC1a gene. These polymorphisms show to have significant
effects on Huntington’s pathogenesis in multiple studies. Interestingly enough, a polymorphism

10. in the promoter region of the gene leads to approximately four years earlier onset while a
polymorphism in the 3’UTR of the PPARGC1a gene transcript is associated with a three to five
years delay of onset [23]. The influences of these polymorphisms on Huntington’s disease onset
are uncertain. However, knowing that up-regulation of PGC-1a beneficially influences
Huntington’s disease onset, and vice versa, a hypothesis can be made on how these onset
variances are occurring. Since the promoter polymorphism leads to a four year earlier disease
onset in Huntington individuals, this polymorphism likely decreases PGC-1a gene expression;
perhaps by lowering PPARGC1a promoter affinity for transcription factors necessary for gene
expression. On the other hand, because the 3’UTR polymorphism leads to a three to five years
delay of onset in Huntington’s disease, this polymorphism may create greater mRNA transcript
stability. In this way, there are greater amounts of PGC-1a transcripts being translated, thereby,
increasing PGC-1a protein concentrations. Varied disease onset in relation to certain gene
sequences within the PPARGC1a gene ultimately gives further support for the association of
PGC-1a in Huntington’s disease pathogenesis [24]. All in all, there is positive evidence in using
PPARGC1a as a therapeutic target to protect Huntington’s individuals from the harmful effects
associated with mitochondrial dysfunction.
Modulating modifier gene influences through pharmaceutical or supplementation
strategies can combat Huntington’s disease onset. There is promising evidence to suggest the
mismatch repair genes MSH2/MSH3 and MLH1/MLH3 increase Huntington’s disease
pathogenesis through more efficient somatic expansion, so therapeutic suppression strategies of
these genes have potential in being beneficial. Targeting the mismatch repair proteins in such a
way to eliminate their function is likely impractical. This is because mismatch repair genes
provide beneficial repair to DNA damage. Furthermore, mutations that render mismatch repair

11. genes ineffective are strongly related to cancer onset [25]. However, this doesn’t rule out the
possibility of suppressing the MSH2/MSH3 and MLH1/MLH3 genes at a level that doesn’t
render them ineffective for normal day-to-day function, while providing a delay in Huntington’s
onset. A study done only on the MSH3 gene in Huntington’s disease mice conveys the idea of
down-regulating MSH2/MSH3 and MLH1/MLH3 gene expression in order to benefit
Huntington’s disease individuals. In this study, elimination of a single MSH3 allele’s worth of
protein sufficiently reduced the mice’s CAG expansive course. Exact methods of targeting all
MSH2/MSH3 and MLH1/MLH3 mismatch genes in a similar way in humans needs to be more
extensively explored. However, practical strategies with a comparable outcome of decreased
efficiency of somatic expansion could be highly beneficial to individuals with Huntington’s
disease [16]. Likewise, PGC-1a over-expression has shown promise in providing neuroprotective
effects in numerous studies. Therefore, pharmaceutical or nutritional supplements that enhance
the expression or effects of PGC-1a would be beneficial to Huntington’s disease individuals.
There are multiple promising methodologies in modulating PGC-1a. This includes activation of
PPAR nuclear receptors through ingesting thiazolidinediones, corresponding to increased PGC-
1a levels, or activating a gene called AMPK through administering guanidinopropionic acid, also
corresponding to increased PGC-1a [13]. An interesting and relatable study even emphasized the
use of a common B vitamin called nicotinamide in enhancing PGC-1a’s activity in Huntington’s
mice. An explanation for such increased activity can be found through a separate gene called
Sirt1 that is found to be up-regulated through administration of nicotinamide [26]. Studies done
on the up-regulation the Sirt1 expression showed deacetylation effects on PGC-1a that increased
PGC-1a’s activity and, in fact, neuroprotection was observed in these Huntington’s mice [27].
The evidence suggest pharmaceutical or nutritional supplementation, such as uptake of

12. nicotinamide, guanidinopropionic acid and/or thiazolidinedione, have potential in delaying
Huntington’s disease onset through influencing modifiers.
What seems to be an essential task for the use of modifier genes as a form of therapeutic
intervention for Huntington’s disease is to gain a better understanding of the disease and the
mutant huntingtin protein interactions within cells. Data on mismatch repair genes MSH2/MSH3
and MLH1/MLH3 demonstrates the genes’ modifying influences on somatic expansion of the
mutant huntingtin gene CAG repeat. Reducing the expansion efficiency of the huntingtin CAG
repeat, which suppression strategies on mismatch repair genes may result in, is an appealing
therapeutic strategy for delaying Huntington’s onset. Further investigation on the mismatch
repair genes may one day provide a practical answer for intervention. Research on PPARGC1a
shows encouraging evidence for targeting the gene in order to provide protection to Huntington’s
individuals from the harmful effects associated with mitochondrial dysfunction. Methods in
enhancing PGC-1a expression or activity have promising potential in delaying disease onset.
Modifications of genes with modifying influences on Huntington’s pathogenesis could delay or
inhibit Huntington’s disease onset. Huntington’s disease is currently incurable; however, there
are great odds that there may one day be modifier gene methodologies to fight its destructive
path.

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