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74 Cards in this Set

  • Front
  • Back
What is an STR, and what is the most common one?
short tandem repeats;
usually CA, but can be trinucleotide. Normally not in coding regions, but can alter transcription if they are abnormally extended, like Fragile X
What is a VNTR?
variable number tandem repeat
Is a SNP a VNTR?
No
Is a STR a VNTR?
Yes, STRs are a subset of VNTRs
Is a VNTR a RFLP?
Yes, causes defferent sized bands on Southern blot.
What is an endophenotype?
A subphenotype within a more broad condition. For example, endophenotypes for diabetes include high blood pressure, central adiposity, high LDL
Name 3 different types of studies that might be used to identify genes associated with a particular disease
linkage (quantative trait loci), candidate gene studies, genome-wide association studies
Why don't linkage studies historically work well for genetic association studies (trying to find genes associated with disease)?
Because there is often high evidence of linkage, but the region containing the loci is enormous, very hard to narrow down what's in it.
Name some important considerations for GWAS.
Hardy-Weinberg must work
Avoid hidden stratification
Big numbers
Allele freq. of 5-10% (not too rare)
Be able to replicate results
Relative risk about 1.1-1.2
Environment is a huge confounder
What is the incidence of new mutations in gametes for Duchenne?
1 in 10,000
What population is most susceptible to Duchenne
None-no bias exists
How large is the Duchenne gene? How does this compare to average gene size?
2.5 million base pairs--100X times larger then average gene size
In some families with Duchenne, a non-carrier mother can have multiple affected children. How?
High rate of gonadal mosaicism in Duchenne
What is the standard rate of recombination (how many crossovers per # of base pairs?)
1% recombination per 1 million base pairs
How does the Duchenne intragenic recombination rate compare to that of most genes?
~12%, which is 5X higher than it should be
Explain the difference in protein production per cell for a carrier of an X-linked recessive mutation vs. a carrier of an autosomal recessive mutation
X-linked recessive--each cell makes either 0% or 100%. AR=all cells make 50%
How was the Duchenne gene mapped?
Physical mapping due to female translocations and male deletions, all on Xp21. Female carriers with X translocations had skewed shutdown of the normal X, so had DMD.
3 steps of positional cloning for a gene
1. linkage analysis or physical landmarks like translocations or deletions
2. Find transcript unit/gene using regions homologous to model systems, find mRNA in cDNA library
3. clone and sequence cDNA, establish genotype-phenotype correlation, ID protein
Currently, DMD deletions are detected how? How were they previously identified?
MLPA analysis. Used to be PCR or Southern.
What % of dystrophin mutations are deletions? What % are point mutations?
70% deletions
30% point mutations
When trying to diagnose DMD in a fetus, and when the family mutation is unknown, what else can be done?
fetal muscle biopsy, test biochemically
Haldane's rule: p2 + 2pq + q2 becomes what?
p2 + 2pq + q
q=affected males, assume there are no q2 females
The 3 protein domains in dystrophin are actin-binding domain, central rod domain, and the carboxy terminal domain. Which are most important in terms of what cannot be deleted to cause DMD vs. Becker?
The actin-binding and carboxy domains are more critical, and deletions that include these regions are more likely to cause severe DMD. The central rod domain is less important and these deletions are usually associated with less severe phenotypes.
What does dystrophin do?
surrounds the long muscle fiber, supports plasma membranes so they don't get destroyed. interacts with many other proteins, which can also cause muscular dystrophy if mutated.
Laminin, which normally interacts with dystrophin, is associated with what condition when mutated?
AR congenital muscular dystrophy (CMD)
What is measured in blood to assess carrier status of Duchenne?
CKs (creatine kinase)
What serum test would suggest that a mom is a DMD carrier?
2 consistent high CK tests
In determining the likelihood that a mom is a DMD carrier, which is more important--CK levels or mutation status?
mutation status trumps all else!
Can people with Becker MD reproduce?
Yes. Daughters will be carriers, sons will not.
Why is it so important to properly diagnose Becker MD with respect to counseling?
Because Becker and other limb-girdle MDs have similar clinical phenotypes,and X-linked recessive and AR inheritance is very different.
Why are conditions like NF and TSC so variable in phonotype, even within families?
Genetic modifiers of rate of 2nd hit, which causes the tumors, cafe spots, Lisch nodules, etc.--2-hit model
In haploinsuffiency disorders, why are modifier genes and environmental factors so important?
When precise levels are so important, other influences can have a big effect
Clinicla features assoc. with hemochromatosis
cirrhosis of liver
fatigue
endocrine failure and diabetes
loss of libido and impotence
can lead to liver disease and cancer, heart disease
2 treatments for hemochromotosis
phlebotomy and hormone replacement
Population at highest risk for hemochromatosis
Northern European Caucasians
Explain sexual dimorphism in hemochromatosis
5:1 male to female penetrance
Relationship btwn alcohol and hemochromatosis
greatly increases risk of penetrance--about 80% of affected have alcohol use
Gene assoc. with hemochromatosis
HLA-A3 allele
When does hemochromatosis typically present?
Post-reproductive years
Why was it hard to find the gene assoc. with hemochromatosis?
Narrowed down to a huge region--some studies placed it mear centromere, others near telomere; there was a huge amount of linkage disequilibrium.
What percent of Notrther nEuropeans carry the C282Y allele for hemochromatosis?
6.4%
What is the most common allele thqat causes hemochromatosis, and what % of alleles are this?
C282Y
85%
Gene assoc. with hemochromatosis. What does the normal gene product do, and how is it changred in hemochromatosis?
HLA-H
Normally associates with transferrin receptor to increase its affinity for iron. Mutant does not associate properly and the receptor has weakenedcaffinity for iron, leading to more iron left in the blood.
Hemochromatosis--the HLA-H protein is expressed where?
everywhere, but highest in gut and liver
Name the top 2 most common childhood neuromuscular diseases
1. DMD
2. SMA
Carrier freq. of SMA among Caucasians
1 in 50
Primary symptom of SMA
muscular atrophy
Which cells are affected in SMA?
anterior horn cells of spinal cord
Most common fatal disorder of infancy
SMA
Describe features of SMA type I
Werdnig-Hoffman
neonatal death
Describe features of SMA type II
intermediate, late-childhood onset, early impairment of walking
Describe features of SMA type III
ugelberg-Welander
late-childhood onset, variable phenotype
Location of SMA gene.
5q
Explain the genes involved in SMA
2 genes--SMN1 (or SMNt) and SMN2 (SMNc). The mroe important is SMN1, and is best correlated with disease. SMN2 is a semi-functional pseudogene, with exon 7 being most important.
Methods used to diagnose SMA
MLPA
Disease assoc. with knockout of androgen receptor
testicular feminization
All polyglutamine trinucleotide repeat disorders work how?
polyglutamine toxicity, dominant gain-of-function makes poisinous protein
What condition is associated with gain-of-function of the androgen receptior due to polyglutamine repeat expansion?
Bulbospinal muscular atrophy (Kennedy's disease)
Cause of spinocerebellar ataxias
polyglutamine repeat toxicity
Polyglutamine repeats typically occur in what part of the protein?
amino-terminus
Fragile X repeats expand through which germline?
maternal
Features of adult-onset myotonic dystrophy
low set ears, myotonia, distal wasting, endocrine problems, difficult personality
If you suspect myotonic dystrophy in a newborn, who else would you check?
Mom, who may have a mild form. Can expand through maternal germline.
Know that both meiotic and mitotic instability of repeat disorders are very common when we get into the pathological size range. Making the jump that creates too many repeats is a rare event, but once we're in the pathological range, there are all kinds of meiotic and mitotic mutations that occur. RNA polymerase looses track of where it is.
Look into this more.
Name 2 recessive, loss-of-function disorders caused by repeat expansion
Friedreich's ataxia, Fragile X
The connexin proteins are what types of proteins?
gap junction proteins--loss of gap junction prevents recycling of toxic ions and metabolites awy from hair cells, leads to their death
What skin findings can be associated with congenital hearing loss?
palmarplantar keratoderma, keratitis-ichthyosis-deafness syndrome
Most common Connexin 26 mutation in whites? asians? AJ?
whites=35delG
asians=235delC
AJ= 167delT, del35G, compound hets with one Cx26 and one Cx30
What is Lamin?
A structural component of the nuclear envelope. Controls stability of nuclear envelope, but also maintenance of transcriptional programs
What make sup the Lamin A/C protein?
2 different protein isoforms from the same transcript unit (same gene)
Differnce btwn Labin A/C and Lamin B
B in undifferentiated cells, A/C in differentiated cells
Inheritance of Lamin A/C disorders
Most are dominant (missense). Different missense mutations in same gene cause different phenotypes/disorders
Features of the Lamin A/C disorder Emery-Dreifus muscular dystrophy
progressive weakness/wasting, cardiac conduction defect = pacemaker by 20 years
Name 3 dominant Lamin A/C disorders
Emery-Dreifus, lipodystrophy, peripheral neuropathy