huntingtons disease Flashcards
gene at play in Huntington disease
IT15 gene, HTT gene
the HTT gene generally has many
CAG repeats
in CAG repeats
repeats itself many times in a row in a gene
every healthy HTT gene has
a genotype with repeated HTT
CAG codes for what
amino acid glutamine
with more CAG repeats
the string of glutamines a protein is longer
too much CAG repeats leads to
a variety of cellular issues (especially in nerve cells)
examples of cellular issues cause by too many CAg repeats
issues with nerve signaling and mitcochondria
neurons with too many copies of glutamines
will malfunction and die
normally functioning HTT gene
10-35 CAG repeats
maybe Huntington HTT gene
36-39 CAG repeats
how many CAG repeats to get Huntington’s disease
40 or more
people with 27-35 CAG repeats
can’t get HT, children can inherit abnormal gene and develop HT
how could children get HT if parents did not have it
in meiosis, repeats are sometimes added or removed
the more CAG repeats the earlier
the earlier the Huntington disease starts
when proteins fold
sometimes there is a mistake
proteins are escorted by what
cellular proteins called a chaperone
what does the chaperone do
serves as quality control, making sure the protein is folded properly before guided to destination
if the protein does not appear to be folded correctly to the chaperone,
the chaperone calls for its destruction
how does the chaperone call for destruction
calls for the attachment of four or more signalling proteins to ubiquitin
adding four or more ubiquitin
polyubiquitination
any protein that has polyubiquinated
does not get escorted to its target site , it is taken to a proteasome
sole function of proteasome
shred proteins who carry polyubiquitination signal
after being the proteasome the peptides are
further broken down by other structures so the amino acids can be reused
peptides
short chains of amino acids
huntingtin
the protein HTT gene codes for
huntingtin carries
many glutamines in a row, (ecspecially mutant huntingtin)
one letter abbreviation for glutamine
Q
glutamine is….
polar (remember like attracts like)
the _____ region from one huntingtin is _______-__
the polyQ region from one huntingtin is chemically attracted to the polyQ region of another huntingtin
in many cases, huntingtin proteins or protein fragments from the polyQ region will
aggregate
aggregate
stick together
chaperones see aggregated huntingtin proteins as
misfolded, and try to ubiquinate them for destruction by proteasome
the aggregates of huntingtinm can sometimes
end up clogging a proteasome instead
how do aggregates clog proteasome
idk , relatively unknown
once proteasomes are clogged by aggregates
a positive feedback loop of aggregated huntingtin starts- they all start aggregating together
Aggregation of huntingtin or its fragments
build up in large amounts, ecspecially in nerve cells
why does aggregation of huntingtin happen a lot in nerve cells
where HTT gene is expressed in the highest amounts, most huntingtin
aggregations have been observed in
- nuclei
- cytoplasm
what usually aggregates in the nuclei
fragments
what usually aggregates in the cytoplasm
larger fragments and full proteins
aggregations eventually grow so large
that cells cannot properly send signals, build microtubules,etc
after large aggregations neruons will begin to
begin atrophy
atrophy
waste away
nerve death from Huntington begins
at various ages depending on the number of CAG repeats
how much of the brain is affected by huntington inclusions
the entire brain
what is the first region of the brain to see neuronal death
the striatum
more neuroanal death is seen
on the dorsal side
the dorsal side oversees
motor function
Huntington’s patients slowly lose
motor function, and eventually behavioral and cognitive function
other name for Guevedoces
5ARD
what happens around 6-8 weeks after fertilization
an embryo will decide what sex it will become
what forms first after fertilization
the internal genitalia
internal genitalia
gonads
what forms second after fertilization
tubes that connect the gonads to the external genitalia
what forms third after fertilization
the external genitalia
in early embryos, what distinct ridges of cells form
Wolffian duct, Mullerian duct
when does Wolffian duct and Mullerian duct form
a fter 5-6 weeks
the wolffian duct has the potential to turn into
a series of tubes that connect the male gonads to the penis- epididymis, vas deferens, seminal vesicle
males gonads
testes
the Mullerian duct has the potential to turn into
a series of tubes that connect the female gonads to the vagina
female gonads
ovaries
the ridges of the Wolffian Duct and Mullerian duct form near
undeveloped gonads, but also connect to the kidneys
gonads can turn into either
the etstes or ovaries
the decision of what the gonads turn into comes from
whether or not the SRY gene is expressed
SRY codes for
SRY protein
what is SRY protein
Sex-determining Region Y protein
SRY is on what chrosome
the Y chromosome
which gender expresses the SRY gene
biological males
SRY protein stimulates what
undifferentiated progenitor cells in the primitive gonads to “grow up”
SRY stimulates undifferentiated progenitor cells to grow up into what
into Leydig and Sertoli cells
where are Leydig and Sertoli cells found
the testes
after 6 to 7 weeks if gonad cells haven’t been hit with SRY….
they decide to grow into ovaries and develop into granulosa cells
Turner Syndrome Patients
also have ovaries
young Sertoli found are only found
only in the testes
young sertoli cells have the unique ability to
express a gene called teh AMH gene
where is the AMH gene found
on chromosome 19, NOT Y
AMH gene codes for
AMH
AMH is
Anti-Mullerian Hormone
AMH works to
stop the development of Mullerian duct
AMH makes the Mullerian duct
wither away into nothing
After AMH does its job, the Wolffian ducts then
then grow into the “male” tubes-epididymis, vas deferens, seminal vesicle
if AMH is not produced…..
the Wolffian ducts degrade and the Mullerian ducts grow into fallopian tubes and the uterus
what are steroids
a class of hormones that are ll synthesized from cholesterol
steroids are all
very close ins tructure
one steroid is often the
precursor of another
now that the gonads have developed,
embryos have either Leydig cells or granulosa cells
what mainly is produced by Leydig cells
androgens
what is mainly produced by granulosa cells
estrogens
testosterone is a direct precursor to
the estrogens
testosterone is also a precursor to
androgen DHT
DHT
dihydrotestosterone
by about 10 weeks
the internal anatomy has decided its fate, the external anatomy will begin to take place
what plays a major role in the process of external anatomy taking place
sex hromones
by 10 weeks the gonads have formed so……
now there are either Leydig or granulosa cells present
Leydig or Granulosa cells each make
a different type of steroid
the bundle of cells that will develop in the external genital have many
androgen receptors
testosterone can bind to and activate
bind to and activate androgen receptors
DHT is a far stronger
agonist of androgen receptors
because DHT is a strong agonist of androgen receptors
a small amount of DHT goes a long way in the formation fo a penis
enzyme that converts testosterone into the extra potent DHT is called
5a-reuctase
gene of 5a-reductase
SRD5A2
SRD5A2 is found
on the 2nd chromosome
SRD5A2 is NOT found where
on the Y chromosome
in people with guevedoces
each copy of SRD5A2 carries an amorphic mutation
when both copies of SRD5A2 carry an amorphic mutation
no DHT is ever produced in these people
people with guevendoces end up developing
ambiguous external genitalia that more closely resemble female genitalia than male
at the beginning the gonads
begin producing high amounts of sex hormones
remember that hormones
come from the gonads
boys, even boys with guevedoces
have testes with Leydig cells inside, they will crank out large amounts of androgens at puberty
in all males
DHT is not very biologically important in puberty or normal “male” activity
the most important androgen in puberty
testosterone
major processes that happen in puberty (males)
growth of the penis and testes
the growth of the penis and testes is catalyzed by
testosterone
during puberty in guevedoces
the previously small penis and scrotum begin to grow. sometimes they descend from the urogenital area
for people with guevedoces, puberty
proceeds as if they were male
long-term consequences of guevedoces
- no breast development-muscle tone similar to other men of the same age
- the ability to produce functioning sperm*
- the ability to reproduce**
people with guevedoces can only produce functioning sperm if
the testes descend (otherwise it is too hot)
people with guevedoces can only reproduce if
the penis forms long enough for intercourse, or other transferring methods of sperm
A person with XY chromosomes, but an amorphic mutation to the SRY gene
ovaries
, vagina
person w/ XY chromosomes amorphic mutation to AMH gene
gonads: testes
fallopian tubes and uterus
A person with XX chromosomes but a chromosomal translocation mutation where the SRY gene is present and active on their 1st chromosome
testes, penis
maple syrup urine disease is
a rare autosomal disease
MSUD is categorized as
metabolic and catabolic disorder
two parts of metabolism
anabolism, catabolism
anabolism
building molecules
catabolism
breaking apart molecules
in most cases symtoms of MAPUD begun
a few days after birth
primary diagnostic symtom of MAPUD
urine with distinct sweet aroma, like maple syrup
MUSD affects how many births
1 in 150,000
because MSUD is recessive
both copies of a gene must be faulty
the MSUD protein is a
trimer
three genes that could be faulty in MSUD
one on chromosome 19
one on chromosome 6
one on chromosome 1
msud gene on chromosome 19
BCKDHA
BCKDHA makes what
E1-a protein
MSUD geen on chromosome 6
E1-B protein
musd gene on chromsome 1
DBT, makes E2 proteins
E1-α, E1-β, and E2 come together to form
a trimeric enzyme
what trimeric enzyme does E1-α, E1-β, and E2 form
branched-chain alpha-keto acid dehydrogenase
important note for MSUD
does not follow dominant negative gene action
it has been proposed that BCKD has
4 subunits, not 3
BCKD
branched-chain alpha-keto acid dehydrogenase
TO GET MUSD YOU MUST
inherit two faulty versions of the same chromosome
_______ catalyzes an irreversible step of the breakdown of three “branched chain” amino acids
Branched-chain α-keto acid dehydrogenase
what branched amino acids are catalyzed by Branched-chain α-keto acid dehydrogenase
valine, leucine, isoleucine
the breakdown of the thee “branched chain” amino acids is a
3 step of 4 step process
failure of BCKD leads to
excess amount of the three amino acids
failure of BCKD also leads to excess byproduct…
alpha-keto acids
keto-acids have
a before the name
mostly, what are valine, leucine, isoleucine used
they are usually used to build the body’s own amino acids
what chromosme is HTT
4th
valine, leucine, isoleucine are brok en..
apart for energy in certain instances
what instances are valine, leucine, isoleucine broken down
- starvation/fasting
- fighting illness
- body consumed too much protein
almost all pieces of the breakdown of valine, leucine, isoleucine
end of falling into the Krebs cycle
what is the Krebs cycle
the complex process in which a cell produces energy from glucose
since pieces of breakdown of valine, leucine, isoleucine join…
join cycle late, means they dont generate as much energy as the sugar
Krebs cycle is responsible for
for energy production of cells
what are the krebs cycle pieces that come from the keto acids
Acetyl-CoA, Succinyl-CoA
when valine, isoleucine and their alpha-keto acids accrue in the bloodstream…
they move into cells
when valine, isoleucine and their alpha-keto acids accrue in the bloodstream and move into cells
it is toxic for cells, ecspecially nerve cells
when the amino acids and their alpha-keto acids move into cells, why is it toxic?
three amino acids and keto acids block entry of other amino acids into the brain (much like in PKU)
having too much of the three amino acids and not enough of the rest leads to
temporary mental retardation, impaired motor control, seizures
the extra byproducts (keto acids) are someties broken down to
to form sotolon
what is sotolon
a small chemical that smells strongly of maple syrupor fenugreek
how is sotolon excreted
through urine
amino acid breakdown is almost completely carried out where
in the mitochondria of liver cells
1 of the cures for MSUD
complete liver transplant `
why can a complete liver transplant cure MSUD
the new transplant cells do not carry the mutation, and can produce E1-a, E1-b, and E2 correctly
before a liver transplant, people w/ MSUD must
closely monitor their diets to avoid protein
why must ppl w/ MSUD closely monitor their diets to avoid protein before a liver transplant
they should have just enough valine, leucine, and isoleucine to produce their proteins
ppl w/ MSUD undergoing a liver transplant must also
avoid going into starvation mode, usually eat MSUD diet powder
why avoid going into starvation mode (MSUD transplant)
so the body dosen’t break down protein for energy, it must stay in first gear and break down carbohydrates constantly
classifications of MSUD
Acute MSUD, Intermediate MSUD, Intermittent MSUD
Acute MSUD
two amorphic or severe hypomorphic mutations inherited for any one of the pieces f the trimer
In acute MSUD symptoms are
present almost immediately after birth and results in death within the first few months of life unless treated immediately
severe hypomorphic
less than 8% function
intermediate MSUD
one piece of the trimer receives two hypomorphic (8-15% function) mutations.
in intermediate MSUD, function of the trimer
is slow, but still work `
in intermediate MSUD, symptoms begin
in childhood, but when depends on how hypomorphic and patients diet
phosphorylation
adding a phosphate group to the R-chain
phosphorylations generally turn proteins
on or off
phosphorylations are almost always
reversible
kinase
an enzyme that adds a phosphate group
phosphatase
enzyme that removes a phosphate group
kinase and phosphate can both be
on or off switch
less extreme forms of MSUD exist
in mutations of 2 other genes BCKDK and BCKDP `
BCKDK does what
codes for BCKD kinase
what does BCKD kinase do
adds a PO4 to the -3 to BCKD
BCKDP does what
codes for BCKD phosphatase
what does BCKD phosphatase do
removes a PO4 to the -3 from BCKD
in the liver,
BCKDK gene is expressed in cells at very low rates compared to other cells
Why does BCKDK code for the off switch (remember it is expressed at low rates)
the liver is the main site of branched-chain amino acid breakdown» we want this enzyme ON in the liver - so the OFF switch will be expressed at low rates here» its the off switch`
BCKDP – when it suffers a hypomrphic mutation
- similar symptoms to intermittent MSUD
- when the liver needs to turn on all of its inactive copies of BCDK, it can’t
what happens when inactive copies of BCDK can’t be turned on
leucine, isoleucine, valine and their keto-acids build up in the body, leading to a short period of MSUD symptoms
after a period of time with inactive BCKD
liver cells produce completely new BCDK trimers that aren’t off yet, patient returns to normal
BCKD phosphatase turns
BCKD on
BCKD kinase turns
BCKD off
when BCKDK suffers a hypomorphic mutation
opposite of MSUD
opposite of MSUD
instead of BCDK not working it works too much
result of opposite of MSUD
branched chain amino acids are broken down instead of being used to build proteins
big symptom of opposite of MSUD
cachexia
what is cachexia
“wasting away”
the loss of muscle mass and/or the failure to add new muscle mass
Intermittent MSUD
Like intermediate, trainer functions at 15+ % efficiency
Intermittent MSUD symptoms
Episodes rare, life can be normal w a proper diet. Episodes often accompany infections
Angelman syndrome defined by
mental impairment, excessively happy demeanor, jerky movements, sleep disturbance
what jerky movements in angelman are common
hand flapping
how many ppl are affected by angelman
1 in 20,000 live births
does Angelman SYndrome present the same phenotype in its patients
yes
the multiple mechanisms for angelman phenotype
imprinting and deletion
imprinting errors
uniparental disomy
genetic imprinting
when one copy of a gene is “turned off” after it is inherited
genetic imprinting is usually caused by
methylation
methylation
additon of methyl group -CH3 o a gene
the methyl group in genetic imprinting does what
blocks transcription from happening> DNA never becomes RNA>never makes protein
(imprinting) for many genes, either the mother’s chromosome or the father’s chromosome is
systematically silenced
what is a gene always silenced in sperm, not in eggs
UBE3A
where is UBE3A located on
on the 15th chromosome
UBE3A codes for
protein E6-AP
E6-AP is involved in what
the ubiquitination process
what is ubiquitination process
cell’s way of targeting and destroying certain proteins
since the father’s copy of UBE3A is always silenced,
the mother’s copy becomes extremely important
in about 75% of cases of Angelman
a chromosomal deletion mutation leads to the complete deletion of this gene in the egg
if there is a deletion of UBE3A in the egg
since the father’s copy is silenced the baby will have no functioning copies of E6-AP
UBE3A gene is located very close to
P gene (causes type 2 albinism)
since UBE3A is so close to P gene
chromosomal deletion mutation will affect both genes» albinism more common in people with Angelman
what percentage of Angelman is an imprinting error
20%
what is the imprinting error that causes Angelman
the mother’s copy of the gene is methylated w/ the fathers
result of imprinting error
both copies are off, phenotypes look the same as if mom’s gene is missing
rare cases of Angelman syndrome
caused by uniparental disomy
uniparental disomy is
rare condition where . zygote inherits two copies of a chromosome from one parent and no copies from another
two forms of uniparental disomy
uniparental isodisomy
uniparental heterodisomy
uniparental isodisomy
when a person inherits the SAME chromosome from a parent twice
what cases would uniparental isodisomy happen
where a person would have a monosomy but undergoes a monosomy rescue
what is a monosomy rescue
the single chromosome is duplicated
a person who underwent a monosomy rescue will have
46 chromosomes, but 2 identical copies of the same one
uniparental heterodisomy occurs when
there would be a trisomy but the zygote undergoes trisomy rescue
trisomy rescue
one copy of the tripled chromosome discarded
in how many cases of trisomy rescue will the embryo be normal
2/3
in _____ cases of trisomy rescue___
1/3 cases, the embryo could inherit two copies of one parent’s chromosomes
uniparental disomy can be the cause of AS when
-a person inherits 2 copies of father’s 15th chromosme, none from mom
when 2 copies of father’s 15th chromosome inherited
both copies of father’s UBE3A gene silenced by methylation,»_space;> AS phenotype
AS rember
3 unique genotypes lead to same phenotype
albinism
lack of pigment melanin
two main types of albinism
- oculocutaneous albinism
- ocular albinism
oculocutaneous albinism
affects skin, hair , eyes
ocular albinism
eyes only
people w/ oculocutaneous albinism have ..
extremely fair skin, white-blonde hair, light blue eyes
melanocytes do what
produce black pigment melanin that makes skin look dark
melanocytes produce more melanin in response to
more sunlight exposure
melanocytes package small amounts of melanin into
vessels called melanosomes
melanosomes are passed on tp
superficial keratinocytes
what does melanin do
absorbs UV rays from sun that can give u cancer
skin color is determined by what
fatctor of number f melanosomes, how active melanocytes are
what does NOT determine skin color
number of melanocytes
A melanocyte generally ha
ling projections called dendrite that reach to more superficial layers
dendrites of melancyte,…
passes melanosomes into outer cells
albinism often causes
red eyes, ,
albinism red eyes…
because w/ a total lack of pigment blood vessels in your can be seen, sensitive too sun
what type of disorder is albinism
recessive
most common mutation for oculocutaneous albinism comes in on
TYR gene on chromosome 11
TYR gene codes for
enzyme tyrosinase
two types type 1 of albinism
Type 1A: Amorphic mutation in TYR
Type 1B: Hypomorphic mutation in TYR
types of type 1 of albinism look
same at birth, usally type 1b is more dirty blonde
tyrosinase is
an enzyme that catalyzes an important step in the synthesis of melanin from tyrosine
without tyrosinase
melanin’s precursor can’t be mDE, MELNIN CAN’T BE MADE EITHER
melanin’s precursor `
dopquinone
type 2 oculocutaneous albinism
comes from a deficiency in a transport protein found in the membrane of melanocytes
the transport protein in the membrane of melanocytes
allows other proteins like tyrosinase to pass into the melanocyte from other cells, causing more melanin to be prduced inside
gene for the transport protein in membrane of melanocyte
P gene, found on 15th chromosme
the other types of albinism come from
mutations in other enzymes in the melanin synthesis pathway , not as common
the other types of albinism can also come from
issues w transportation in melanocytes, storing melanin correctly etc
ho many different genotypes of albinism have been seen
ho many different genotypes of albinism have been seen
htt is found on
chromosome 4 :)
