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424 Cards in this Set

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What is genetic anticipation?
a phenomenon in which disease severity increases and/or age of onset of disease decreases from one generation to the next (builing upon expansions)
How is genetic anticipation depicted in Souther blot?
grandfather will not have phenotype of disease but has premutation. His daughter will receive normal transmission and not have the phenotype of disease, but since her germ cells have the expansion(she is a carrier), it will be passed down to her son and he will be affected: see large fragments
how many unstable NT repeat disorders are there in humans?
40
what is the repeat for FRAXA? where does it occur?
CGG
5'UTR
What is the repeat for FRDA? Where does it occur?
GAA
intron
What is the repeat for HD? Where does it occur?
CAG
exon
What is the repeast for SCA? Where does it occur?
CAG
Exon thefore affects protein syn: glutamine expansion
What is the repeat for DM? where does it occur?
CTG
3'UTR
Length of repeat determines what?
severity of disease
What is the normal range for FRAXA? pathogenic?
normal : 6-60
pathogenic: >200
What is the normal range for FXTAS?
normal : 6-60
pathogenic: >50
What is the normal range for FRDA? Pathogenic?
normal: 6-32
pathogenic: 200-1700
What is the normal range for HD? pathogenic?
normal: 11-34
pathogenic: 40-121
What is the normal range for SCA? pathogenic?
normal: 6-39
pathogenic: 40-82
What is the normal range for DM? pathogenic?
normal: 5-37
pathogenic: 50-1000
What are normal alleles in tandom repeat expansion?
not associated w/ disease and stable upon transmission
What are mutable alleles in tandom repeat expansion?
DO NOT cause disease, but show meiotic instability (sex specific)
What are reduced penetrance alleles in tandom repeat expansions?
late onset and meiotic instability
What are disease alleles in tandom repeat expansions?
associated w/ disease
meiotic instability and for some diseases also mitotic instability
Which alleles in tandom repeat expansions are the largest? smallest?
largest: disease alles
smallest: normal alleles
What is the basis for dynamic mutations?
repeat instability (expansions or contractions of simple seq repeats)
what are dynamic mutations?
dynamic mutation is an unstable heritable element where the probability of mutation is a function of the number of copies of the mutation. That is, the replication product of a dynamic mutation has a different likelihood of mutation than its predecessor.
What is anticipation?
the tendency of age of onset to decrease and severity of symptoms to increase through successive generations of an effected family due to the expansion of these repeats.
What is similar about al 40 of the dynamic mutations?
all neurological diseases
mostly triplet repeats
Do longer tracts or shorter tracts show a greater likelihood of undergoing repeat expansion?
longer tracks
what does repeat length correlate w/?
disease severity and age of onset
What causes an expansion?
hairpin loop in NEW strand (replicating daughter strand) due to backward slippage causing insertion
result: too many repeats on replicating strand
What causes a contraction?
hairpin loop in TEMPLATE strand (parent strand) due to forward slippage causing deletion
What is dynamic instability?
tendency of expanded dna tracts to form anomolous DNA structures-intrastrand hairpins
*key req for dyanamic mutations
What is slipped intermedate DNA?
the strands (template and daughter) have different numbers of repeats
looping out of the okasaki fragments results in?
expansions
looping out of template strand causes?
contractions
in what types of cells is repeat instability occuring?
proliferating cells
quiescent cells
meitoic cells
there is a similarity b/n instability threshold and what?
okasaki fragment length
What type of repair machinery repairs the looped out structures in proliferating cells?
RPA (single stranded binding protein) recognizes looped out structure
unwinding by helicases
nuclease activity (FEN-1 (removes RNA primer from Ok fragment) and DNA polymerase)
What type of repair machinery repairs the looped out structure in quiescent cells (not dividing)?
mismatch repair genes (Msh2 and Msh3) recog the looped out structure (DNA repair p)
structures repaired w/ same proteins involved in prolif cells (Helicase, FEN-1, Polymerase)
What diseases show a paternal expansion bias?
HD and SCA
*most CAG expansions (polyglutamine disorders)
Germline instability can be caused by what 3 factors?
meitotic recombination
DNA replication
DNA repair
what are the most likely causes of Paternal expansion bias?
errors in replication and/or repair NOT meitotic recomb b/c mutations were already found in mitotic diploid germ cells
In which diseases do we see a paternal contraction bias?
GAA repeat in FRDA
CGG repeat in FRAXA
(FRAXA males inherit a single maternally expanded allele that experiences germ-cell specific contractions)
Maternal expansion bias is chara. of what diseases?
CGG expansion in FRAXA
C(C)TG expansions in DM
What is the cause of maternal expansion bias in FRAXA?
mutational event during recombination b/c length mosaicism is rare in premuation to full mutation transmission
What is the cause of maternal expansion in DM?
combo of replication errors, repair errors in oocyte prophase I and somatic instability
Which diseases can have further expansions in adults?
HD and DM
Which disease is not present in fetal tissues?
HD
which disease is not present in adult tissues?
FRAXA
which disease are loss of fxn (loss of protien) mutations?
FRAXA, FRDA
Which diseases are gain of fxn (altered PROTEIN) mutations?
HD, SCA
Which disease are gain of fxn (altered RNA fxn) mutations?
DM1, DM2, FXTAS(only older males)
What is the inheritance of FRAXA?
X, dominant
What is the inheritance of FRDA?
AR
What is the inheritance of HD?
AD
What is the inheritance of SCA?
AD
What is the inheritance of DM?
AD
What type of DNA testing can be done for dynamic mutations?
PCR for normal range repeats (6-60)
Souther Blot if repeats >400 (PCR will not work)
How many primers are needed for DNA testing of dynamic mutations?
2: forward and reverse PCR primers
Use ECOR1 to digest
When DNA testing for dyanamic mutatons, what do you use as a probe for southern blot?
use the repeat as probe
What do you use as the probe for PCR when testing for dynamic mutations?
single copy seq for probe
What disease does this describe? muscle weakness in arms and legs, vision, hearing and speech problems
-dramatic spine curvature
-diabetes
-serious heart condition
-wheelchair by late teens
FRDA
What characterizes FRDA?
wheelchair bound by late teens
muscle weakness in arms and legs
dramatic spine curavature
Dx b/n age 5 and 15
Which disease shows a defect in transcriptional elongation?
FRDA
What is the problem in FRDA?
splicing slowed down b/c large expansion (200-1700)of GAA in intron
FRDA shows a decreased protein production of what?
Frataxin
what is the most commonly inherited ataxia?
FRDA (AR)
why is anticipation not oberved in FRDA?
b/c it is AR
*severity and freq does not increase w/ generations
which allele is expanded in FRDA? which allele defines the severity of the disease?
both! it is AR so both the maternal and paternal alleles are expanded but different thus affected will have phentype of shorter expanded allele (the better allele)
the severity of disease in FRDA is mostly defined by which allele?
shorter allele--shorter expansion therefore more protein production
*age of onset and severity associated w/ repeat length
98% of FRDA alleles are GAA expansions, the rest are what?
point mutations (allelic heterogeniety >different mutations in same gene)
Why is there seen a excess of iron in mitochondria of FRDA?
b/c frataxin is needed for heme biosynthesis and formation of Fe-S clusters
in which disesae do we see a reduced fxn of respiratory chain complexes I-III and aconitase with excess free radical formaion and energy deficiency?
FRDA
what disease (other than Downs) is a genetic cause of inherited mental retardation?
FRAXA
what disease accts for 4-8% of all males w/ learning disabilities?
FRAXA
incidence of FRAXA?
1/5000 males
1/25000 females (less severely affected)
What disease is evident cytologically?
FRAXA by fragile site (area of expanded triplet repeat) in X chromosome
What disease was the first description of a triplet instability?
FRAXA
Clinical features of FRAXA in adult males?
delayed developmental milestones
prepubertal: MR, speech delay, hyperactivity, autism, tantrums, abnormal craniofacies (long face, large ears, prominent forehead and jaw)
POSTpubertal: macroorchidism (large testes), abnormal behavior: shy, aversion
strabismus (lazy eye), joint hyperextensibility, pes planus (flat foot)
MVP, smooth skin
clinical features of FRAXA in females?
heterozygous females
same physical and behavioral features but lower freq and milder involvement
50% penetrance
How is FRAXA cytogenic diagnosis done?
1. in cultured cells on folate-def medium to inhibit replication of chrom
2.chromosomes are stained and the X chrom has a non-staining constriction site near the distal end of q (Xq27)**non staining does not indicate lack of DNA, chrom is not broken it just doesnt stain completely
what percentage of pts with all the clinical signs of FRAXA are negative for the fragile site?
less than 1%: they have pt mutations or gene deletions
Why named Fragile X?
more fragile sites on X chrom
Does FRAXA demonstrate anticipation?
yes, severity and freq increase w/ the generations
what is true of normal grandfathers of a FRAXA grandson?
they must be carriers, have premutation, the grandfather and his daughter are negative for Fragile site b/c premutation alleles are not fragile
What is the expansion bias of FRAXA?
maternal : due to meiotic recomb problem; unstable when going thru female meiosis; no expansion in sperm!
Does having the premutation for FRAXA indicate learning difficulies?
no they do not have the fragile site and are of normal intelligence
protein of FRAXA?
FMR
protein of FRDA?
frataxin for heme biosynthesis
explain the mech of FMR1 transcriptional suppression via CGG repeat exapnsion
1. expanded repeats are methylated
2. MeCP2 binds to hypermethylated CGG repeats and forms complexes w/ HDAC via repressor Sin3
3. HDAC deacetylates histone H3 and H4 of the chromatin around CGG repeats
4.histone deacetylation leads to chromatin condenstaion and transcription repression "silencing"
why is FMR suppressed in FRAXA?
the CGG repeats are hypermethylated...methylationturns genes off
What protein contains RNA binding domains?
FMRP
what does FMRP associated w/?
RNA targets in the nucleus to form RNP's and is transported to dendritic spines
in what disease will we see abnorm large dendritic spines?
FRAXA
99% of FRAXA is cuased by __? 1% caused by?
99% large expansion of CGG
1% missense: isoleu-asparagine
What is LTD?
weakening of neuron synaptic connextions b/n neurons in the hippocampus and is reqd for memory and learning
What counteracts LTD? HOw?
FMRP
LTD breaks synaptic connections and FMRP reforms them. W/o FMRP there is a decresae in the plasticity of the brain leading to inefficient learning and memory
LTD is brought about by ?
metabotropic glutamate R's thus drosphilia deficient in FMRP that are given inhibitors of glutamate R's (decrese the breaking of synapes) show good results
IN what population do we see FXTAS?
older male premutation carriers
what is the pathological hallmark of FXTAS?
eosinophilic, ubiquitin positive intranuclear inclusions in neurons and astrocyts throughout brain
you see a buildup of what in FXTAS?
FMR1 RNA in inclusions
2-5 fold increase in mRNA but reduced translation
the increase of FMR1 mRNA in FXTAS disrupts what?
lamin
A CGG sequence in the FMR1 gene that is repeated about 55 to 200 times is described as what?
premutation
do not have fragile X syndrome, but are at increased risk of developing a disorder known as fragile X-associated tremor/ataxia syndrome (FXTAS
females w/ FMR1 premuation get?
premature ovarian failure
FXTAS exhibits:
age-dependent penetrance
if you are affected w/ FXTAS in your 5th decade, what is the penetrance?
17%
if you are affected w/ FXTAS in your 6th decade, what is the penetrance?
38%
if you are affected w/ FXTAS >80 years old, what is the penetrance?
75%
FRDA and FRAXA are both due to null muations that are cuased by?
mostly repeat expansions
or pt mutations or deletions
what is the protein for DM?
DM protein kinase gene (DMPK1)
clinical features of DM?
myotonia, muscle wasting, weakness
cataracts
hypogonadism
frontal balding
abnormalities on EMG
insulin resistance due to splicing
Does DM show anticipation?
yes, through mother, maternal expansion bias
freq of DM?
1/8000
which form of DM shows congenital cases?
only DM1
cuase of DM1? DM2?
DM1: CTG expansion in 3'UTR
DM2: CCTG expansion in intron 1
what gene do you see teh expansion for DM1?
DMPK1 gene on chrom 19q
what gene do you see the expansion for DM2?
ZNF9 gene on chrom 3q
Which form of DM is a Founder affect suggested?
DM2 families of German descent
What is the pathogenic mech of CUG repeats?
expansion cuases haripin loop to form that titrates out RNA binding protein that is necessary for correct splicing of OTHER proteins
What is not the path mech of CUG repeats? what is this mechanism called?
not caused by export of expanded CUG transcripts being blocked..the body can do w/o the DMPK gene, but can't fxn w/ abnormal splicing of other proteins
*Trans dominant RNA-mediated abberrant splicing
what explains the multi system defects in DM?
gain of fxn due to altered RNA fxn
What are some proteins that are affected by abberant splicing in DM?
insulin R: insulin resistance
Chloride channel: myotonia
cardiac troponin T: cardiac abnormalities
Ryanodine R's: muscle wasting
HD causes loss of ?
loss of moter fxns, death of motor neurons
HD is due to ?
N terminal expansion glutamine repeats in EXON
In HD, death is how many yeras from age of onset?
15yrs
Are HD and SCA loss of fxn or gain of fxn?
gain of fxn (altered protein fxn) b/c occur in exon
What can you use to diagnose HD?
PCR- onto polyacrylamide gel
PCR: small lenght fragments
Southern: large length fragments
What are the HD allelic types?
normal: 27 repeats
mutable instability: 27-36
reduced penetrance: 36-39
disease: 40+ repeats
what chrom is HD affecting?
4
which disease is an adult onset disease?
HD
*age of onset correclated w/ # of repeats, more repeats, earlier onset
40 CAG HD repeats is what age of onset? 45 repeats? 50 repeats?
40:57 years
45: 37 years
50: 27 years
what diseae shows cerebellar w/ variable involvement of brainstem and spinal cord?
SCA
clinical features of SCA are caused by?
degeneration of the cerebellum and its afferent and efferernt connections which involve brainstem and spinal cord
when is pt wheelchair bound in FRDA? SCA?
FRDA: late teens
SCA: w/n 20 years after 1st symptoms
what is the penetrance of SCA dependent on?
age: clinical signs start at 20-30 years in 10% of the patients and 70 year old gene carriers have all clinical signs
*the older you are, the more penetrant the disease is (like FXTAS)
how many different loci are defined for SCA?
25
7 of them show exonic expansion of CAG
what disesase are considered polyglutamine diseases?
HD and SCAs
in polyglutamine diseases, how can different neurological genetic disesase arise like HD and SCA?
b/c diff neuron pop. are vulnerable
what is the pathological feature of polyglutamine diseases?
insoluble aggregates or inclusions due to long polyglutamine tracts not effecienlty degraded
what is the fxn of the inclusions seen in polyglutamine diseases?
they are protective (vulernable cell pop show no inclusions). those that escape the inclusions are translocated to the nucleus where they interfere w/ p53 and interfere w/ transcription
what is the mech. of polyglutamine disease?
NOT through cellular inclusion formation, but through interference w/ transcriptional regulation
1. mutant expanded proteins interact abnormally w/ HATs or HDACs interferring w/ histone modification and gene expression
2. several TFs and co acivators such as p53 are depleted by sequestration into aggregates
what is the action of HDAC inhibitors in polyglutamine diseases?
turn on certain genes, like p53
size of nuclear genome? mt genome?
nuclear: 3 billion bp
mt: 16.5 K bp
# of different DNA molcules in Mt DNA?
1 circular DNA molecule of dsDNA
how many MtDNA copies/cell? per mt?
thousands of copies / cell
5-10 copies/ mt
Number of genes in nuclear genome? mt?
nuclear: 25,000
mt: 37
what do the 37 mt genes code for?
2: rRNA
22: tRNA
13: mRNA (structural genes)
What do the 13 structural mt genes code for?
protein subunits in ox phosphorylation *the most important fxn of the mt
what are the 2 strands of mtDNA called?
H strand and L strand
H is G rich (purine which is heavier)
L is C rich (pyrimidine)
What are the features of the Displacement loop of MtDNA?
triple stranded (7sDNA: short H strand fragment)
Origin of replication for H
Promoters for both strands
Only non-coding part of the mtDNA
what is the fxn of 7S DNA in D loop?
primer for dna polymerase for H
why is the D-loop triple stranded?
because a short segment of the heavy strand is replicated for a second time, giving a structure known as 7S DNA
a vast majority of mitochondrial oxidative phosphorylation system is encoded for by what genome?
nuclear
What does the Mtgenome rely on the nuclear genome for?
The mitochondrial genome encodes all the ribosomal RNA and tRNA molecules it needs for synthesizing proteins but relies on nuclear-encoded genes to provide all other components (such as the protein components of mitochondrial ribosomes,
describe the replication of the L strand.
replication of the L strand proceeds in the opposite direction, using the H strand as a template
the mRNA genes of mtDna are separated by what?
tRNA genes
rRNA genes are juxtaposed
What portion of H strand is coding? L strand?
H: all coding except for D loop
L: codes for 1 mRNA and several tRNA
describe the transcription of mtdna?
continuous unlike nuclear in which most genes are transcribed indididually w/ TFs
how many subunits of Complex I (NADH dehydrogenase) are encoded by mt? nuclear?
mt: 7 subunits
nuclear: 40
how many subunits of Complex II (Co Q reductase) are encoded by mt? nuclear?
mt: 0
nuclear: 41
how many subunits of Comple III (cytochrome b-c1) are encoded by mt? nuclear?
mt: 1
nuclear: 10
how many subunts of complex IV (Cyt C oxidase) are encoded for by mt? nuclear?
mt: 3
nuclear: 10
how many subunits of complex V (ATP synthase) are encoded for by mt? nuclear?
mt: 2
nuclear: 14
how many components of the protein syn apparatus for mt are encoded for tRNA?
mt: 22
nuclear: none
how many components of the protein syn apparatus for mt are coding for rRNA?
mt: 2
nuclear: none
how many components of the protein syn apparatus for mt are coding for ribosomal proteins?
mt: None
nuclear: 80
how many copies of mtDNA does the mammalian egg contain? sperm?
egg: 100,000
1/3 of total dna content!
sperm: 100
why aren't sperm mt. transmitted/
b/c they are marked w/ ubiquitin, selecting them for degradation upon entrance into the oocyte
what is heteroplasmy?
if a mutation arises in a copy of mtDNA, a mixed intracellular pop of mutant and normal mtDNA develops
*co-existence
how does heteroplasmy occur?
when cell divides by fission and each mtDNA replicates and randomly distributes b/n 2 daughter mt. then the mt. randomly segregate b/n 2 daughter cells
what is replicative segregation?
over time the % of mutant mtDNA of diff cell lineages can drift towards pure mutant (when threshold reached) or pure normal
Desribe the process of amplification. when does it occur?
amplification of maternal mtDNA from low copy in primordial germ cells (50)to high copy in the mature oocyte (100,000mtDNA) and its dilution to approximately somatic cell levels during formation of the blastocyst(1,000mtDNA/cell)
*takes place when primordial germ cells progress to primary oocytes and subsequently to mature oocytes
when does restriction (bottleneck) in number of mtDNA to be transmitted occur?
post fertilization of mature oocyte . oocyte has 100,000 mtDNA molecules but following fertilization, there is a reduction in the number of mtDNA copies/cell
bottleneck cuases what feature of mtDNA?
heteroplasmy b/c only a few mtDNA molecules populate the organism then undergo amplification
is mt DNA or nuclear DNA more variable?
mt.: variations consist of SNP's and small deletions/insertions
accumulation of polymorphisms occurs 10 fold faster compared to nucler DNA
EX: D-loop is extremely polymorphic
How are new mitochondrial mutations fixed ?
bottleneck plays an impt role in fixing the mutations in the population
how many different mtDNA rearrangements and point mutations have been identified?
100 mtDNA rearrangements
50 different pt mutations
incidence of all mt disorders?
1/8500
What are the 3 primary types of mtDNA mutations?
1. rearrangements that generate deletions or duplicatoins in the mtDNA
2. point mutations in tRNA and rRNA that impair mt. protein synthesis
3. missense mutations in the coding regions of genes that alter ox. phosphorylation activity
what is similar about mtDNA mutants?
they are heteroplasmic: coexistence of normal and mutated mtDNA in the same cell/tissue *varies widely in differnt tissues
at what point does someone that is heteroplamic show disease phenotype?
until critical threshold of % mutated is exceeded
are lethal mutations heteroplasmic or homoplasmic?
some mutations in mtDNA are never found in homoplasmic form : letal mutations
how much of the mtDNA is normally deleted in Kearns-Sayre and Pearson?
4-6Kbp
*may be up to 7000 bp encompassing essential genes, like tRNA genes
Deletion mutations of mtDNA are always found in what state?
heteroplasmic and sporatic
how do you detect mtDNA deletions?
w/ PCR or Southern blot
the types of deletion mtDNA mutations are based on what?
presence or absence of bone marrow involvment
Which mtDNA deletion mutation is w/o bone marrow involvment?
Kearns-Sayre sydnrome
Which mtDNA deletion mutation is w/ bone marrow involvment?
Pearson sydrome
Kearns-Sayre shows deletions where?
in muscle tissue, not in blood
Pearson syndrome shows deletions where?
in all tissues even BM thefore anemic
what will you see in Kearns-Sayre syndrome?
typical ragged red fibers that contain <80% mutated mtDNA
clinical signs of Kearns Sayre?
progressive external opthalmoplegia (external eye mm paralyzed), retinopathy, cerebellar ataxia, heart block
Pearons' syndrome shows what finding?
pancytopenia (reduced # of RBC, WBC, and platelets)
Sideroblastic anemia (abnormal prod of heme components)
exocrine pacreatic failure
what is the problem in MELAS?
base substitution in tRNA genes in mtDNA
substitution of LEUCINE
Features of MELAS?
always heteroplastic
short stature
stroke like episodes: vomiting, headaches, visual disturbances
Diabetes
sensorineural hearing loss
maternally transmitted
what does MELAS stand for?
mitochondrial encephalomyopathy, Lactic Acidosis, and Stroke-Like episodes
why do you see genetic and allelic heterogeneity in MELAS?
b/c multiple genes coding for Leu therefore: genetic b/c disease caused by different genes
allelic b/c different mutations in same gene give same disease
What is the problem in MERFF?
base substitution in tRNA coding for LYSINE
features of MERFF?
heteroplasmic
progressive myoclonic epilepsy and seizures
maternall transmitted
What does MERFF stand for?
Myoclonus Epilepsy and Ragged Red Fiber
what is the problem with LHON?
missense mutations in subunits of Complex I
which mt. disease might be homoplastic?
LHON
What does LHON stand for?
Leber's Hereditary Optic Neuropathy
Features of LHON
may be homoplastic
subacute painless bilateral visual failure
male/female ration of 4/1
X chromosome has an impact on penetrance
age of onset ~24 years
is LHON more common in males or females?
males: 4/1
What is the problem with NARP?
mutation in ATPase 6 gene in subunit 5 of Complex V of ox phosphorylation
what does NARP stand for?
Neurogenic muscle weakness, Ataxia, Retinitis Pigmentosa
onset of NARP?
late childhood or ADULT-onset
What is the problem with Leigh syndrome?
maternally inherited more severe form of NARP w/ more mutated mtDNA: problem is ATPase 6 gene of Complex V
difference b/n NARP and Leigh?
NARP: adult onset
Leigh: childhood onset
mutations in the tRNA for lysine results in?
MERFF
mutations in the tRNA for Leucine results in ?
MELAS
missense mutations in the Complex I subunit genes result in?
LHON
Describe the Log age of onset vs % heteroplasmy graph
linear regression
more mutated mtDNA earlier onset
LHON, NARP and Leigh are all what?
missense mutations in protein coding genes
A loss of DNA repair genes is what type of inheritence? Ex?
AD
Li-Fraumeni syndrome
What is the problem in Li-Fraumeni?
germline mutation in tumor suppressor p53
What explains the autosomal dominant inheritance in Li-Fraumeni?
second hit hypthesis: individuals unsually inherit one mutant copy of the p53 tumor suppressor gene and the second mutation occurs sometime during life in a target cell.
What does Li Fraumeni increase the chance of?
Increases the severity of cancer..cancer often strikes at a young age, many diffrent forms of cancer
Why do people with the same p53 mutation get different cancers?
b/c of second hit hypothesis:an individual as a germ line mutation in one allele for tumor suppressor gene can overtime develop a somatic cell mutation. Now those cells have 2 mutated p53 genes. depending on what tissues the mutated cells are present in will determine the type of cancer
why is loss of tumor suppressor gene considered AD inheritence?
Unlike oncogenes, where a mutation at one allele is sufficient for malignant transformation in a cell, both copies of a tumor suppressor gene must be inactivated in a cell for malignant transformation to proceed.At the cellular level, tumor suppressor genes behave recessively. However, at the organismal level they behave as dominants
What is p53?
guardian of the genome
tumor suppressor gene
TF acting at G1 limiting entry into S phase
-role in activating apoptosis
What percent of tumors are p53 mutations found in?
>50% of all tumors and in > 50 different types of tumor
<10% of all colorectal cancer is due to what ?
Hereditary Non Poliposis colorectal cancer (HNPCC)
What causes HNPCC?
mutations in all 6 mismatch repair genes: most freq MLH1 and MSH2
inheritance of HNPCC?
AD
HNPCC defects in DNA mismatch repair lead to what?
microsatellite instability
what is the lifetime risk of heterozygous males for HNPCC gene of developing colorectal cancer?
90%
what is the lifetime risk of heterozygous females for HNPCC gene of developing colorectal cancer? what else are they at risk for?
70%
40% risk of endometrial cancer
is mutation in mismatch repair genes involved in HNPCC gain or loss of fxn?
loss of fxn
loss of fxn in the second copy of HNPCC gene allele will cause what?
defective mismatch repair leading to an increased mutation rate and cancer
MSH2 and MLH1 are genes mutated in what ?
HNPCC
Microsatellite instability is a characteristic feature of what?
HNPCC
How many human homologs of E coli MutS or MutL genes have been implicated in HNPCC?
five human homologs of the E. coli MutS or MutL genes have been implicated in cancer
Why do >29% of microsattelites tested in HNPCC show instability?
Because DNA mismatches are more likely to occur in DNA microsatellites (areas with multiple repeats of one nucleotide or one pair of nucleotides), defective DNA MMR leads to the phenomenon of microsatellite instability, in which the progeny of the defective cells have varying lengths of a given microsatellite.
What is the fxn of MSH2 and MLH1 repair genes?
Genes in the mismatch repair (MMR) pathway are responsible for identifying and repairing single nucleotide mismatches and insertion or deletion loops that occur as cells grow and divide
What are microsatellites?
stretches of DNA with a repetitive sequence of nucleotides (e.g., AAAAA or CGCGCGCG) that are particularly susceptible to acquiring errors when mismatch repair gene function is impaired. Cancers arising in cells with defective mismatch repair gene function exhibit an inconsistent number of microsatellite nucleotide repeats when compared to normal tissue, a finding referred to as "microsatellite instability."
Describe the steps in mismatch repair.
1. mismatches or loops are recognized by MSH2/MSH6 dimers
2.MSH2/MSH6 dimers translocate and bind MLH1/PMS2 dimer
3.complex of the 2 dimers strips back and resynthesizes a new strand w/ the help of exonucleases, DNA pol and replication factors
How does the MMR determine which base is the mismached base (which strand)?
parental strand is methlyated at A bases and sensed by MutS
15% of all colon cancers exhibit what?
microsatelite instability
microsatellite instability is more freq in tumors from patients who WHAT?
develop cancer at a younger age
what percent of women in N. America develop breast cancer in their life time?
10%
what increases the risk of developing breast cancer?
if a first degree relative is affected
what percent of breast cancer has a strong genetic component?
20%
what percent of breat cancer is due to dominantly inherited, early onset Mendelian predisposition?
small proportion : 5%
What are the major genes identified for familial breast cancer? what other cancer are they associated w/?
BRCA1 and BRCA2
ovarian cancer
BRCA1 is found on what chromosome? BRCA2
17
Many distinct germ line BRCA1 mutations have been identified, although most of the mutations result in the synthesis of what?
truncated BRCA1 protein
Fxn of BRCA1 and BRCA2?
both NUCLEAR proteins
fxn in same multiprotein complex to repair ds breaks that result from damage
Which gene, BRCA 1 or 2 accts for 1/2 of the AD familial breast cancers?
BRCA1
Which gene, BRCA 1 or 2 accts for 1/3 of the AD familial breast cancers?
BRCA2
Which BRCA gene confers high risk for ovarian cancer and predisposes to prostate and colon cancer?
BRCA 1
Which BRCA gene confers high risk for ovarian cancer and high risk for male breast cancer?
BRCA2
What normally are the mutations in BRCA1and 2 genes?
small frame shifting deletions or insertions, splice site mutations or deletions of one or more whole exons (non sense mediated decay)
What ethnic origins are known to be founder mutations for BRCA 1 and 2?
Ashkenaski Jews
Iceland
African Americans
What is the inheritance of Nijmegan breakage syndrome?
very rare AR
what are some clinical features of Nijmegan breakage syndrome (NBS)?
chromosome breakage
growth retardation
microcephaly
immunodef
cancer
Where does linkage anaylysis pinpoint Nijegman Breakage syndrome?
8 Mbp region on chromosome 8p21
How was the small region containing the NBS gene discovered?
Nibrin is the gene
ancestral haplotypes can be identified and used to define the exact position of the disease gene.
Which disorder shows An ancestral haplotype in European patients?
NBS
What ancestral haplotype is NBS associated w/?
Slav origin
What is the inheritence of Ataxia TElangiectasia? adult of childhood disorder?
AR
childhood disorder
What disease exhibits cerebellar ataxia and dilated blood vessels in the white of the eye, ears and face)?
Ataxia Telangiectasia
patients with Ataxia Tel hve a increased riske for what?
30% risk of lymphoid cancer
Ataxia Tel pts. have an increased sensitivity to what ?
ionizing radiation
What is the gene responsible for ataxia telangiectasia ? Therefore whats the problem?
ATM; phosophokinase involved in phosphorylating p53 which stops cell cycle from progressing from G1-S. W/O ATM don't have cell cylce break
What components make up the BRCA1 associated genome surveillance complex (BASC) that repair ds breaks?
Nibrin, MRE11 and Rad50
Nibrin comlexes with MREII and RAD50 at ds break
MRE11, a component of BASC, is mutated in what?
AT -like syndrome: later onset and slower progression, very rare
inheritance of Bloom syndrome?
AR disease of childhood
characteristics of Bloom Syndrome?
small body size
light sensitive facial rash
predisposi to lymphoma and leukemia
ultrasensitive to chemo
in which disease do you see an incrased rate of sister chromatid exchance?
Blooom sydrome
inheritence of Werner syndrome?
AR
problem in Werner?
premature onset of age-related phenotypes, including cancer
which AR syndrome shows hypersensitivity to agents taht interfere w/ DNA replication?
werner
the genes for Werner and Bloom code for what?
DNA helicases which appear to be crucial for correct recovery from replication arrest
why do replication forks stall? if they stall what can happend?
as a consequence of endogenous damage of the propensity of repeated sequences to form tertiary structures. Stalling can give rise to DNA ds breaks formation, and chromosomal rearrangements
What is the inheritence of Fanoconi anemia?
AR childhood disorder
characteristics of child with Fanconi anemia?
upper limb abnormalities
increased pigmentation
BM failure; pancytopenia
Faconi anemia patients have an increased risk for what?
leukemia, lymphoma, and hapatic carcinoma
problem in Fanconi anemia?
general defect in repairing ds breaks in the DNA
Describe complementation assay for FA
The diagnosis of FA rests upon cytogenetic testing for increased chromosomal breakage or rearrangement in the presence a bifunctional DNA interstrand cross-linking agent mitomycin C (MMC)
What does the Fanconi anemia (FANC)repair pathway consist of?
2 complexes
Complex 1: E3 ligase activates FANCD2
Complex 2: DNA damage-inducible repair Foci including BRCA1 and BRCA2
Explain the steps of Fanconi DNA repair pathway.
DNA damage activates ATR which p-lates Complex 1. Complex I then ubiquinates the FANCD2 protein. Ubiquinated D2 then recruits BRCA1, BRCA2 and other proteins in Complex 2 (DNA damage-inducible repair foci). Then DNA is repaired and a ubiquinating enzyme inactivates FANCD2
What activates Complex I of the Fanconi anemia DNA repair pathway?
DNA damage activates ATR which then p-lates Complex I
What is the inheritence of Xeroderma Pigmentosa?
AR
What is the major cause of death in XP?
skin malignancy in sun-exposed areas, 2000-5000 higher risk for malignant melanoma
What is the problem in XP?
is a genetic disorder of DNA repair in which the body's normal ability to remove damage caused by ultraviolet (UV) light is deficient.
Nucleotide excision repair defect of pyrimidine dimers caused by UV light
When do you see chromosomal abnormalities in cultured XP cells?
when you challenge the cells with UV light
How many complementation groups of XP are there? Most common? Which is the most sensitive to UV?
7 XP genes: A-G
XP-C most common, pts. show only skin disorders
XP-A is the most sensitive
Explain the nucleotide excision repair
The damage( bulky lesions like pyrimidine dimers) is excised by exonucleases, then the gap is filled by a DNA polymerase and sealed by a ligase. The
Fxn of XP-C?
distortion recog of T-T dimers
Fxn of XP-B?
helicase activity and subunit of TF IIH
Fxn of XP-D?
helicase acitivity..form open bubble
Fxn of XP-G?
nucleases to nick on the 3' side of DNA lesion
Fxn of XP-F?
nuclease to nick on the 5'side of the DNA lesions
What is the fxn of RPA in Nucleotide excision repair?
protein that binds to single strand DNA
What does mismatch repair correct? what happens if any of these genes are mutated?
corrects replication errors
mutation: microsatellite instability and HNPCC
What causes Nucleotide excision repair? Base excision repair?
NER: mutagenic chemicals or UV light
BER: damage from the inside like ROS
What diseases are involved in mutations of repair of ds strand DNA breaks? (6) which is the only one that is not a cancer syndrome?
Nijmegen Breakage
AT
Bloom
Werner*aging not cancer
Fanconi anemia
BRCA1/2 breast cancer
all cancers are..
genetic (involve change in DNA)
Def of cancer?
progression from a normal somatic cell to a pop of proliferating and invasive cells via a mutlistep mutational and selective pathway
Even when there is a clear environmental effect associated with cancer, know that it acts by ..
MUTATION (cuasing change in DNA seq that affects cell growth)
what increases one's risk of cancer?
more affected relatives, greater risk for next person in family
Ex: 3 or more 1st degree relatives affected: 1 in 2 chance
Breast syndrome is affiliated with what types of cancers?
breast, ovary, colon, prostate
Li Fraumeni syndrome is affiliated with what types of cancers?
sarcoma, breast, brain, leukemia, adrenal cortex
MEN2 syndrome is affiliated with what cancers?
thyroid (medullary), pheochromocytoma
How does a cell aquire a growth advantage?
with each successive mutation so that it forms an expanded clone, thus presenting a larger target for the next mutation
what are the 3 main groups of genes that are mutated in cancers?
1. DNA repair genes
2. oncogenes
3. tumor suppressors
what does LOHTS GOFONC stand for?
Loss of heterozygosity: tumor suppressor
gain of fxn: oncogene
How do acute transforming retroviruses cause cancer in animals?
usually retroviruses encode 3 genes: gag, pol, env. But when a virus integrates into a host, it could integrate near a normal oncogene. Thus that oncogene is now transcribed by the viral genome and becomes overexpressed.
Ex: SRC, JUN, FOS
what are some general fxns of oncogenes?
induce telomerase activity
block apoptosis
stimulate prolif
increase blood supply
How are oncogenes activated by amplification?
multiple copies of structurally normal oncogenes are formed . a mutational event then drives cell prolif
What are the 4 types of known oncogene activation?
amplification
point mutations
translocation
translocation to generate chimera
Translocation of ABL-BCR on chrom 22 leads to what?
CML: Chronic myeloid leukemia
what is the difference b/n the translocation in CML and Burkitts?
CML: translocation of BCR-ABL generating chimera producing novel product
Burkitts: oncogene coding seq is under the control of another gene: Myc trancloated into an Ig gene
what is the product of the Myc-Ig gene translocation in Burkitts?
myc is now under control of Ig gene and is thus overexpressed but in normal amounts *not making new message
IN what sort of tumors would you be likely to see Burkitss lymphoma?
B cell lymphomas
In what sort of tumors would you NOT expect to see Burkitt rearrangment?
lung, brain where Ig is not expressed
what is the traditional though of oncogene mutations?
that they are never/rarely inherited
what are the 2 exceptions of oncogenes that are inherited?
Multiple endocrine neoplasia 2 and hereditary papillary renal carcinoma
what are the cancer risks involved with MEN2a and 2b?
MEN2a: parathyroid adenoma
MEN2b: mucosal neuromas
MEN is a gain of fxn mutation in what?
tyrosine kinase receptor RET
Hirshprungs is a loss of fxn mutation in what?
tyrosine kinase receptor RET
waht is the difference b/n MEN and Hirschsprungs?
MEN: gain of fxn in RET
Hirsh: loss of fxn in RET
inheritance of MEN:
AD 50:50 chance of inheriting
Hereditary papillary renal carcinoma is a gain of fxn muataion in what?
MET tyrosine kinase
What disease is a gain of fxn in MET tyrosine kinase?
hereditary renal carcinoma
inheritance of hereditary papillary renal carcinoma?
AD
De novo germline mutations in what are the most common cause of Costello syndrome?
HRAS
what is Costello syndrome?
DE NOVO germline mutation!! mismatch mutation in HRAS protein causing overproduction. Instead of triggering cell growth in response to particular signals from outside the cell, the overactive protein directs cells to grow and divide constantly. This uncontrolled cell division can result in the formation of noncancerous and cancerous tumors
what are the phenotype involved with Costello syndrome?
short stature
redundant skin
mental retardation
familial cases involving tumor suppressor genes are almost always ? sporatic cases?
familial: bilateral
sporatic: unilateral
what is the difference in age of onset b/n familal and sporatic tumor suppressor mutatoins?
familial: children b/s germline mutation
sporatic: adult b/c 2 hit hypothesis
what is happening in a familial form of retinoblastoma?
all cells have one mutated copy of the gene,RB1. they then acquire another mutation sporatically that leads to bilateral retinoblastoma
If the hereditary form of retinoblastoma is AD, why dont you see cancer from the mutated gene?
b/c at the molcular level it is recessive b/c a tumor only occurs w/ loss of both alleles. For example, a damaged TSG (such as the Rb1 gene in retinoblastoma) would not lead to cancer unless there is a growth impetus from an activated oncogene. This is b/c development of malignancy is based on the activation of oncogene and deactivation of TSG ie. you need mutations in both the Rb1 genes
when do we see loss of heterozygosity?
in familial cases the second mutation is seen as LOH
explain LOH in retinoblastoma.
mother and father are both homo for 2 different alleles at same locus. mother transmits Rb gene along with allele 2. Dad passes normal Rb at allele 1. Child is constitutively an obligate heterozygote for 1 and 2 at this locus. But analysis of tumor tisse reveals apparent homo for allele 2 therefore loss of paternally derived allele 1
what can you say about the Rb1 gene?
gene product is a negative regulator of cell growth ie TSG
what events can inactive the Rb1 gene in the "good" allele in the 2nd hit?
loss of chromosome through mitotic non disjxn
deletion of chrom carrying allele
cross over b/n 2 homologous gene leading to homo for mutant allele
what are 3 ex of rare familial cancers caused by TSG mutations?
AT
Li fraumini
Rb
however, many genes whose products are involved in DNA repair can be thought of as tumor suppressors since they follow 2 hit model
TSG normally act as?
gatekeepers (cell cycle growth, growth inhibition)
caretakers (DNA repair, genome integrity)
what is p53?
TF acting as G1 limiting entry into S phase
*activates apoptosis
inheritance of neurofibromatosis type I (NF1)?
AD with complete penetrance by age 5
even w/n families, what disease is extrememly variable resulting in 50% cases w/ new mutations?
NFI
which gene codes for negative regulator of the Ras oncogene?
NF1 coding for neurofibromin
what is the inheritance of NF1?
The mutant gene is transmitted with an autosomal dominant pattern of inheritance, but up to 50% of NF-1 cases arise due to spontaneous mutation. The incidence of NF-1 is about 1 in 3000 live births.
characteristics seen in NF1 patients?
truncal freckling, cafe au lait spots, multiple neurofribromata
*Lisch nodules
what does NF1 gene map to? what does it encode?
chrom 17
neurofibromin, GTPase activating protein that acts as neg regulator of RAS (oncogene)
in NF1 do you see G. fxn or L fxn?
L fxn b/c gene tumor suppressor..that is a negative regulator of an oncogene
how many types of neurofibromatosis are there?
2
type 2 is rarer (1:35000)
difference b/c NF1 and 2?
2 is seen in more limited cell population. tumors of 8th cranial nerve developing early in childhood: known as Vestibular Schwannomas
chromosomes of NF1 and 2?
1: 17
2: 22
both AD
NFtype 2 is due to a mutation in what protein?
Merlin (TSG), a cytoskeletal protein acting as a negative regulator of the Hippo pathway
[NF1 is coding for neurofibrin a GTPase activating protein]
majority of colorectal cancers develop from?
benign adenomas ..mutations that accumulate during carcinogenesis
what is the APC gene?
adenomatous polyposis coli in familial ademotous polyposis (FAP)
*APC is a TSG
do you see LOH with APC ?
yes on 5q b/c it is a TSG that is transmitted as AD
colorectal cancer development starts how?
with being heterozygous for APC mutation in germline ( hence familial adematous polyposis)
explain the model of colorectal cancer development?
start with germline mutation in APC. DNA is then hypomethyated leading to activation of KRAS oncogene and development of early adenoma. Another loss of TSG will cause intermediate adenoma. Then loss of p53 causes late adenoma and finally carcinoma
what does APC interact w/ in the nucleus?
nuclear beta catenin (acts to activate the transcription of genes such as cyclin D1 and c-myc in conjuction with lymphoid enchancer factor) APC displaces beta catenin to the cytoplasm where is is degraded by the proteasomal machinery
what happens in the absence of APC in terms of Beta catenin?
w/o APC, beta catenin is free to activate transcription factors like c-myc thus there is ** less negative regulation of beta catenin dependent pathways (more expression of oncogenes like cmyc)
a germline TS mutation can be the cause of wht?
cancer ex: Retinoblastoma
*other mutations cause particular Mendelian syndroms that may not include tumor as part of their presentation
what is the distinction b/n syndromes and cancers?
syndrome: characteristics that run together based on germline mutation
cancer: characteristics that arise due to 2nd mutation somatically
Do diseases that are asociated with cancers show symptoms relating to that cancer?
No no always, Ex: lung and bladder cancer are NOT part of the symptomalogy of Loeys'Dietz syndrome which is associated with lung cancer
does tuberous sclerosis exhibit bladder cancer symptomology ?
no, even though it is associated with bladder cancer
to be a sucessful tumor, cells must become what?
independent of external GF
independent of external anti-growth signals
able to avoid apoptosis
capable of indefinite replication
capable of sustained angiogenesis
capable of tissue invasion and metastasis (metastasis may be second to other features)
what diagnositc infomation can you perform to analyze gene expression?
look at expression pattern of genes and classify them with tumor of origin, look at clustering of gene expression to distinguish 2 types of large cell lymphoma
what is the inheritance of Hutchinson-Gilford Progeria Syndrome?
AD but most mutations are sporatic b/c Progeria pts dont live long enough to have kids
What are the clinical findings of Progeria?
Premature, rapid ageing
micrognathia
alopecia
lack of sub-cutanous fat
artherosclerosis-fatal in teens
age: decade/year
How fast do Progeria kids age?
decade/year
Progeria is most often due to mutation of what?
silent single base substitution in G608 in Lamin A/C due to alternative splicing of LMNA to give Lamin A or C which form heterodimers in nuclear membrane
what is different about Lamin A and C?
different C terminal
The most common progeria results in a ___
cryptic splice site in exon 11 but still coding for glycine
How is Progeria different from Werners and Cockayne syndrome?
it is not due to defective DNA repair:
Prelamin A contains a CAAX box at the C-terminus of the protein. This ensures that the cysteine is farnesylated, and this allows Prelamin A to bind membranes, specifically the nuclear membrane. After Prelamin A has been localized to the cell nuclear membrane the C-terminal amino acids, including the farnesylated cysteine, are cleaved off by a specific protease. The resulting protein is now Lamin A, is no longer membrane-bound and carries out functions inside the nucleus. In HGPS the recognition site that the enzyme requires for the cleavage of Prelamin A to Lamin A is mutated. Lamin A cannot be produced and Prelamin A builds up on the nuclear membrane, causing a characteristic nuclear blebbing.
As a result of the cryptic spice site in Progeria, what is retained and what is lost?
retains farnesylated site
loss of proteolytic cleavage site (cleaves off farnesylated group to make mature lamin)
loss of phosphorylation site
*now you have aberrant interaction with Lamin C
In LMNA mutations, affected tissues are derived from what type of cells?
mesenchymal cells b/c they are more sensitive to deficiency in lamin than other cells (all other cells are still mutated, but most evident in mesenchymal cells)
Normally what is our bodies reponse to a damaged genome?
apoptosis or senescence
*damaged genomes don't get replicated
What is the normal situation in a cell that undergoes DNA damage?
p53 is phosphorylated and stops cell cycle at G1 to allow DSB repair. If repair is done, cell division resumes. If repair can't be done, apoptosis and senescence occur. All result in normal aging, genomic stability, and tissue regeneration
What is the situation in a progeria cell that undergos DNA damage?
Before damage even occurs, the nucleus has blebs and heterochromatin loss, and nuclear pore clustering. Thus the DNA damage is compounded by mechanical stress and HC disorganization greatly increasing the amount of activated p53. Apoptosis and Senescence greatly increase more than normal and less cell division occurs b/c DSB repair is delayed. therefore you get accelerated aging, genomic instability.
What do you NOT see in Progeria?
No cancer (b/c overactive p53 increasing senescence)
No CNS disorder
characteristics of Cockayne Syndrome type 1?
normal prenatal growth
growth and developmental abnormalities w/n 2 years
HT, WT, HC <5%ile
progresive neurological dysfxn
*lifespan 13yrs
ERCC8mutations
Characteristics of Cockayne syndrome type 2?
growth failure at birth
minimal post-natal neur develop
*lifespan 7 yrs
ERCC6 mutations
what is the similarity b/n Cockayne and XP?
both have photosensitivity due to problems in DNA repair
general cockayne characteristics?
cutaneous photosensitivity
leukodystrophy
thin skin, little fat
aged apearance
**AR
What are the 2 genes responsible for Cockayne Syndrome?
The two genes responsible for Cockayne syndrome are ERCC6 (75% of individuals)(CS-II) and ERCC8 (25% of individuals)-CS-I.
What are the actions of the gene products of Cockayne syndrome?
The proteins made by the ERCC8 and ERCC6 genes are involved in repairing damaged DNA by the transcription-coupled repair mechanism, particularly the DNA in active genes
How are XP and CS alike in terms of thier gene products?
RNA polymerase II is stalled during transcription, XPG and CSB respond to the stalled transcription bubble. They then recruit transcription factor II H and other proteins and protein complexes to remodel RNA polymerase, gain access to the bubble, and repair the lesion while leaving polymerase in place.
Why must ERCC6 and 8 have another role in transcription?
b/c CS kids have neurological problems that aren't seen in XP and XP do not exhibit growth retardation
What is Klotho?
It codes for a transmembrane protein that, in addition to other effects, provides some control over the sensitivity of the organism to insulin and appears to be involved in aging. The protein is a beta glucosidase
What is seen in homozymous Klotho mice?
aging like humans: infertility, osteoporosis, arteriosclerosis
alternative splicing of klotho yeilds what form?
secreted variant form that is carried in blood and is associated w/ incrased risk of coronary artery disease
what are telomeres?
nucleprotein structures that cap the ends of eukaryotic chromosomes and prevent checkpoint activation and maintain chromosome stability
telomeres are composed of waht type of repeats?
G-rich NT repeats bound by a complex array of proteins that stabilize formation of looped end
why do telomeres shorten progressively?
b/c DNA pol can't fully replicate the lagging strand
what is the Hayflick phenomenon?
fibroblasts in culture will only live through 50 divisions before telomeres become too short
telomerase is expressed in what cells?
germ cells so that the next generation get a fresh start-sex repro is therefore essential for species w/ linear chromosomes
telomerise is NOT expressed where?
in normal somatic cells so that telomeres shorten w/ successive cell generations and cells stop dividing
what are the 2 essential components of telomerase?
TERC: RNA subunit (template for copying)
TERT: reverse transcriptase that binds TERC and makes telomeres by copying the telomere repeat seq encoded by TERC template
Normally the proteins located in telomeres inhibit what?
TERT in somatic cells preventing unlimited proliferation, but in cancer cells the complex is disrupted and no inhibition of TERT..unlimited prolif
what else can TERT do besides telomere maintenance?
activate resting stem cells through an independent pathway
What 3 features will you see in Dyskeratosis congenita patients?
poor dentition
reticular hyperpigmentation
aplastic anemia
DKC is due to mutations in what?
TERC-AD
DKC1:X linked
TERT:AD
what is observed in DKC?
anticipation in the absence of triplet repeat expansion since an affected individual will transmit short telomeres to offspring and those inheriting a mutation will develop progressively shorter telomeres; phenoytpes result from shorter telomeres
what is teh gene product of DKC? involved in?
dyskeratin
rRNA processing
impt in rapidly dividing cells therefore loss of dyskeratin leads to anemia and skin problems b/c of impact on keratinocytes and BM
*increased apop due to critically shortened telomeres shuts down actively dividing cells
premature aging is due to breakdown in what?
cell maintenance (dna repair, telomere, nuclear integrity)
What are the prenatal screening options?
FIRST
Maternal serum screening
ultrasound
What are the prenatal diagnostic options?
CVS
amniocentesis
ultrasound(detailed)
Fetal blood sampling
Fetoscopy/muscle biopsy
What does FIRST stand for?
First Trimester Integrated Screening for Trisomies
when is FIRST performed?
11-14 weeks gestation
what is considered in FIRST?
maternal serum free hCG and pregnancy associatd Protein A (PAP-A)
Nuchal measurment
Maternal age
What are the detection rates with FIRST of Downs and Trisomy 18?
80% fetal Downs
90% trisomy 18
who is FIRST offered to?
all pregnant women regardless of their age
*do not do prenatal testing based on maternal age..test everyone
what is the risk associated with screening test? diagnostic test?
screening: no risk
diagnositic: risk involved: 1/200
when is maternal serum screening done?
15-20 weeks for AFP, hCG and uE3
What are teh 2 ways in which CVS can be obtained?
transcerival or transabdominal
when is CVS done?
10-14 weeks
Second Trimester maternal serum screening is done when?
15-20 weeks
Second trimester screening measures what?
triple screen: Alpha-fetoprotein (AFP), hCG, and unconjugated estriol (uE3)
occasionally : inhibin A
of the second trimester triple screen, which are obtainined from fetal? placental?
uE3 and AFP from fetal
hCG placental
Second trimester screeings used for detection of:
ONTD (open neural tube defects), trisomy 18, Downs
Increased AFP indicates? decreased AFP?
increased = ONTD
decresed = Downs
Sickle cell is associated with what ethnic group?
blacks
Tay sachs, Canaven, and Gaucher are associated with waht ethnic group?
Ashkenasi Jews
Beta thal is associated with what ethnic group?
mediterranean
alpha thal is associated with what ethnic group?
Southeast Asia
CF is assoicated with waht ethnic group?
Caucasian
What 2 ethnic groups have the same carrier risk for CF?
caucasians and Ashkenasi 1/29
what is the baseline risk for having a child with serious birth defect?
3-5%