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DT4- Exam 3 > Primerano- Genetics x5- Leah > Flashcards

Primerano- Genetics x5- Leah Flashcards

1
Q

What distinguishes a polymorphism from a benign mutation?

A
  • Both polymorpism and mutations represent a “variant” allele
  • Polymorphisms are “variant” alleles carried by more than 1% of the population. (I.e. not just carried by a single person!)
  • Mutations can be carried by a single person, or less than 1% of the population (Bottom line: % population carrying the variant determines polymorphism vs mutation)
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2
Q

What makes a locus polymorphic?

A

-A gene locus with more than 100 possible variations (alleles) is “polymorphic”

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3
Q

What makes a disease or phenotypic trait “monogenic”? What does it mean when a monogenic disease shows allelic heterogeneity? Locus heterogeneity?

A
  • Mongenic: disease phenotype or trait can be caused by mutating a single gene. -Allelic heterogeneity: same or similar disease can be caused by multiple different mutations at the SAME locus.
  • Locus heterogeneity: mutations at multiple locations may lead to the same disease

(A note about locus heterogeneity: DO NOT BE CONFUSED. This does not mean that multiple loci must be changed AT ONE TIME to lead to a disease, it just means that either path A, B, *OR* C may get you to disease A)

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4
Q

–What is an example of a trait that has monogenic inheritance?

–What are 3 examples of diseases with monogenic inheritance? Their inheritance patterns?

–Which of the three diseases have allelic heterogeneity? Locus heterogeneity?

A
  • cell surface antigens (blood groups, HLA antigens)
  • DMD (XR), CF (AR), PKU (AR)
  • DMD and CF= allelic heterogeneity
  • PKU= locus heterogeneity
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5
Q

What is allelic constitution? What are the four types of constitution?

A
  • arrangement of different possible alleles at locus
    1. SAME two HEALTHY alleles at locus = homozygous
    2. Two DIFFERENT alleles at locus= heterozygous
    3. Two different DISEASED alleles= heteroallelic
    4. Two of the SAME DISEASED alleles= homoallelic

Bottom line: suffix –zygous = no disease; suffix allelic= diseased

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6
Q

What is the consequence of the F508 mutation on the CFTR gene?

The F455 mutation?

A

F508: constributes to severe (pancreatic insufficiency) form of CF)

F455: constributes to mild (pancreatic sufficient) form of CF

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7
Q

What are the five possible allelic constitutions in the CFTR gene?

A
  • +/+: homozygous (healthy)
  • F508/+: heterozygous (carrier)
  • F508/F508: homoallelic (severe disease)
  • F508/455: heteroallelic (mild disease)
  • F455/455: homoallelic (very mild disease)
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8
Q

What is the difference between Duchenne and Becker Dystrophy?

What is this an example of?

A

Both cause muscular weakness :

  • Duchenne: large out of frame dystrophin deletion –> complete loss of protein; severe disease and death at 18
  • Becker: small in frame dystrophin deletion –> partial loss of protein; mild disease

Example of monogenic inheritance + allelic heterogeneity! (multiple possible alleles causing same or similar disease)

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9
Q

In addition to Duchenne/ Becker’s Muscular Dystrophies, ______ ______ is an example of a disease with allelic heterogeneity. In addition to being classified as having “allelic heterogeneity”, these diseases could also be called ________.

A
  • CF (Remember; F508 and F455 mutated alleles both cause similar disease with F455 being less severe) -monogenic
  • CF + DMD are MONOGENIC and have ALLELIC HETEROGENEITY!
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10
Q

What kind of stain is used to distinguish Duchenne from Becker’s on muscular biopsy?

A
  • immunofluorescence
  • NO dystrophin in Duchennes
  • LOWERED dystrophin in Beckers
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11
Q

Phenylketonuria results from failure to ________.

97% of cases are caused by a mutation in _______.

3% of cases are caused by mutations in OTHER enzymes.

This is an example of ______ ______.

A
  • Convert phenylalanine to tyrosine
  • 97% = mutation in phenylalanine hydroxylase
  • example of locus heterogeneity (also a monogenic disease because only ONE ENZYME must be lost to cause the disease!)
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12
Q

Type 1 PKU:

  • gene affected?
  • chromosome?
  • dietary restrictions?
A
  • phenylalanine hydroxylase
  • chromosome 12
  • restrict phenylalanine
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13
Q

Type 2 PKU:

  • gene affected?
  • chromosome?
  • dietary restrictions?
A
  • BH4 reductase
  • chromosome 4
  • restrict Phe, LDOPA, and 5HT

**UWORLD QUESTION**

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14
Q

Type 3 PKU: -gene affected? -chromosome? -dietary restrictions?

A
  • Biopterin synthesis
  • multiple possible loci
  • restrict Phe, LDOPA, 5HT
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15
Q

Mitochondrial Inheritance:

  • How many genes?
  • What kinds of functions do these genes have?
  • Describe the pattern of inheritance in mt. disease.
  • Uworld likes to call diseases with mt inheritance an example of ?
  • Primerano calls this an example of?
  • Disease Example:
A
  • 37 genes
  • oxphos, rRNA, tRNA
  • mom to ALL offspring; dad to NO offspring -“heteroplasmy”
  • “replicative segregation” (See picture on pg 5 of his notes)
  • Leber Hereditary Optic Neuropathy
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16
Q

Many traits are determined by the interaction of multiple genes, meaning they have _______ inheritance.

_________ refers to all genes that infleunce the action of the gene in question, which can often explain incomplete penetrance/ variable expressivity.

A
  • Polygenic inheritance
  • Genetic background
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17
Q

What does it mean when a trait is said to have “multifactorial” inheritance?

What are some examples of these traits?

A
  • Multiple genetic and environmental factors interact to give the trait
  • Examples: intelligence, height, weight, Alzheimers, CVD, cancer etc.
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18
Q

Polygenic inheritance often leads to conditions with ______ & _________.

This can most often be explained by ______.

However, incomplete penetrance in Fragile X is explained by ______.

A
  • incomplete pentrance
  • variable expressivity
  • most often due to multifactorial inheritance (more than one gene + environment)
  • *genomic instability*/ *allelic heterogeneity* in Fragile X
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19
Q

Penetrance is the probabiltiy that _____?

What is the equation for penetrance? In “incomplete pentrance”, what is said to determine the presence or absence of a trait?

A
  • trait will be manifested in the presence of a given allele
  • # cases with phenotype/# cases with genotype
  • “either-or” phenomenon
  • most often said to be determined by modifier gene (genetic interaction)
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20
Q

Incomplete penetrance is a characteristic of ______ inheritance.

On a pedigree, diseases with incomplete penetrance appear to ______?

A
  • dominant inhertiance, recessive does not = incomplete penetrance
  • appears to “skip” a generation
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21
Q

CF: complete or incomplete penetrance?

A
  • COMPLETE
  • genotype = 100% chance developing phenotype

(Remember, incomplete penetrance is possible in DOMINANT inheritance, CF is AR.)

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22
Q

Huntington’s Disease: Complete or Incomplete Penetrance? What determines the age of onset?

A
  • AD -COMPLETE penetrance with varying age of onset
  • Age of onset inversely related to the number of trinucleotide repeats
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23
Q

Polydactyly, Brachydactyly, and Fragile X: Complete or Incomplete Penetrance?

A

-Incomplete

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24
Q

Retinitis Pigmentosa is an example of disease with _____ inheritance.

What genes are involved?

What does the disease cause?

A
  • Polygenic inheritance
  • Requires TWO DIFFERENT mutated genes (peripherin and ROM1 photoreceptor proteins
  • Cause of retinal degeneration
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25
Q

Fragile X:

-Describe the prevalence

A
  • most common HEREDITARY form of mental retardation
  • 2nd most common cause overall (#1 = trisomy 21) -1/1250 males
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26
Q

Fragile X:

-What is seen on cytology?

A
  • secondary constriction on X chromosome (fragile site)
  • site has frequent breakage and fails to condense during metaphase

**Note: this is not longer the diagnostic method of choice, but may be tested.

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27
Q

Describe a male with Fragile X:

Female X carrier?

Homozygous female?

A

MALES:

-mental retardation, delayed speech -large head, testes, ears, jaw -stubby hands

FEMALE CARRIER: -may be shy and have learning disorder

HOMOZYGOUS FEMALE: -not seen, Fragile X males don’t mate

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28
Q

Fragile X:

Inheritance Pattern?

Penetrance?

Variation of phenotype in females is due to?

When do repeats “occur”?

A
  • X linked dominant FMR1 mutation
  • CGG trinucleotide repeats at the 5’ region
  • incomplete penetrance w/ % penetrance dependent upon sex
  • variation in females due to EXTREME LYONIZATION
  • repeats generated during meiosis + somatic events (i.e. some X chromosomes may have more repeats than others due to somatic events)
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29
Q

Incomplete penetrance is not a result of polygenic inheritance, but rather _______ in the case of fragile x.

A

-“allelic heterogeneity”

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30
Q

Fragile X pedigree:

  • A phenotypically normal man who passes a disease allele to his offspring is called what?
  • Compare the likelihood that his children will have disease vs his grandchildren. What is this called?
A
  • nonpenetrant transmitting male (NPTM)
  • granchildren more likely to have disease than children (trinucleotide expansion with each generation)
  • Sherman paradox (^ likelihood of disease as you move down pedigree)
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31
Q

Fragile X: Describe the difference between a normal, premutated, and mutated allele.

A
  • normal allele: less than 50 CGG repeats at 5’
  • premutated: 50-200 repeats (low levels FMR1)
  • more than 200 repeats (no FMR1 gene products)
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32
Q

How is Fragile X diagnosed?

A

Southern Blot: detects methylation and size expansions in larger mutations/ fully mutated alleles

PCR: discriminates small differences in pre-mutation alleles

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33
Q

What is the trinucleotide repeat in:

  • Fragile X
  • Huntingtons
  • Myotonic Dystrophy
  • Freidrichs These are all characterized by?
A
  • Fragile X: CGG (See (C) a Gross Guy)
  • Huntingtons: CAG (Hunt animals and put them in the CAGe)
  • Myotonic Dystophy: CTG (“See (C) Tonic Gestures)
  • Freidrichs: GAA (Genetic AtaxiA)
  • genetic anticipation
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34
Q

Does genetic anticipation always cause “sherman phenomenon” on pedigree?

A
  • NO
  • Anticipation can be manifested by increased penetrance of disease with generation OR increased severity (i.e. lower age of onset as in Huntingtons)

bottom line: genetic anticipation does not always = increasing penetrance

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35
Q

What is ascertainment bias?

A
  • False genetic anticipation
  • Diseased individuals in early generations not detected –> causes apparent increasing penetrance
  • (may be caused by lack of proper diagnostic tools etc)
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36
Q

Myotonic Dystrophy:

  • inheritance pattern
  • chromosome?
  • repeat
  • symptoms
  • anticipation?
A
  • autosomal dominant
  • chromosome 19
  • “See (C) Tonic (T) Gestures (G)”– CTG
  • myotonia, ptosis, cataracts, hypogonadism/ balding
  • genetic anticipation (phenotypic worsening)
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37
Q

Expressivity:

Definition?

  • How does this compare to penetrance?
A
  • Expressivity: degree/ type of manifestation of a penetrant gene
  • Penetrance: refers to the PRESENCE OR ABSENCE of manifestation of a diseased allele (either/or phenomenon)
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38
Q

Neurofibromatosis:

Inheritance pattern?

Gene involved?

CLASSIC EXAMPLE OF?

A
  • Autosomal Dominant
  • NF1
  • classic example of VARIABLE EXPRESSIVITY

(same NF1 gene mutation can cause a variety of symptoms varying in severity)

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39
Q

Contrast mild v severe NF:

A
  • mild: cafe au lait spots + neurofibromas
  • severe: thousands of disfiguring neurofbromas, malignant brain tumors, mental retardation (variable expressivity)
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40
Q

Osteogenesis Imperfecta:

  • inheritance pattern
  • penetration
  • expressivity
  • classic symptoms?
A
  • AD
  • 100% penetrance
  • variable expressivity
  • blue sclera, easily fractured, deafness
41
Q

What is uniparental disomy?

A
  • Both copies of a chromosome come from the SAME parent (i.e. two maternal copies of chromosome 15, no paternal copies)
  • EUPLOID karyotype! (23 x 2 chromosomes)
42
Q

What is genomic imprinting?

A

-Chromosome activated or inactivated in a sex-specific manner

43
Q

Two diseases classically used to exemplify uniparental disomy and genetic imprinting?

What chromosome do these diseases affect?

Which disease causes an ANGRY demeanor?

A happy demeanor?

A
  • Angelman Syndrome (AS) and Prader Wili Syndrome (PWS)
  • chromosome 15
  • ANGRY FAT BOY: PWS
  • HAPPY PUPPET: AS
44
Q

-Deletion explains _____% of AS/PWS.

Explain how deletion leads to PWS or AS.

A

70% occur via this deletion method:

  • PWS: PATERNAL (P of PWS) c15 is deleted, maternal c15 is silent
  • AS: MATERNAL (mom is an ANGEL) c15 is deleted, paternal c15 is silent

(silent= genetic imprinting)

45
Q

Deletion accounts for 70% of PWS/AS.

How do the other 30% of PWS/AS cases occur?

A
  • Inheritance of TWO paternal c15’s and NO maternal (AS)
  • Inheritance of TWO maternal c15’s and NO paternal (PWS)

(uniparental disomy)

46
Q

What is a quantitative trait?

What is the most common inheritance type of quantitative traits?

A
  • Trait that can be numerically measured on a continuous spectrum by meters, grams, test scores, etc
  • Multifactorial inheritance (genes + environment)
47
Q

Examples of normal human traits determined by a variety of genes + environmental factors:

A

-skin/ hair color -weight, height -blood pressure -intelligence

48
Q

How is a dichotomous trait different from a quantitative trait?

A

-Quantitative trait is measured on a continuous spectrum (super short –> super tall) -Dichotomous trait is EITHER present OR absent (cleft lip)

49
Q

How can a dichotomous trait be described using a bell curve?

Give an example.

A
  • Bell curve has THRESHOLD point at which a trait will manifest
  • Ex: Pyloric Stenosis: curve based on low –> high liability of disease.

Threshold point on curve marks point where disease DOES OR DOES NOT present (either-or phenomenon)

Liability bell curve based on both genes and environment

50
Q

List five human diseases that are “threshold diseases”

A
  1. pyloric stenosis (risk 5x ^^ in males)
  2. cleft lip and palate
  3. NTD
  4. CVD (genes + exercise diet etc)
  5. Emphysema (a1 anti-trypsin + smoking)
51
Q

Multifactorial Disease:

  • apparent inheritance pattern
  • what is the “gamma ratio”?
A

-family studies suggest inherited disease, but no apparent mendelian pattern exists -yr= prevalence in family/ prevalence in general population

52
Q

Multifactorial Disease:

  • risk of primary family members contracting same disease as affected individual
  • risk of remote relatives?

How does this compare to autosomal dominant conditions?

A
  • primary relatives have risk ~ square root of general population frequency (this makes literally no sense to me but it is what the notes say.)
  • risk RAPIDLY DECLINES for remote family members
  • In autosomal dominant traits, risk of remote family members ~50% of primary family member risk.
53
Q

For multifactorial traits with sex- dependent features, when is the recurrence risk especially high?

A
  • When proband (affected person the study starts with) is the LESS COMMONLY AFFECTED GENDER.
  • I.e. female with a PREDOMINATELY MALE disease! (Suggests higher level of genetic liability)
54
Q

Alzheimers:

Where are NF tangles found?

What are senile plaques caused by?

Genes required for APP processing?

A
  • Tangles: cortex and hippocampus
  • Plaques: Amyloid Precursor Protein ^^^ –> Amyloid deposits

APP processing: presenilin 1 & 2

55
Q

When does early onset Alzheimer’s occur and what is its inheritance pattern?

What mutations are associated?

A
  • Before age 60
  • AD
  • mutations in APP or presenilin 1/2
56
Q

Typical Alzheimer’s is an example of what kind of genetic disease?

Early onset?

A
  • Typical: multifactorial
  • Early Onset: monogenic + locus heterogeneity (can be caused by presenilin 1 or 2, or APP mutation)
57
Q

What is the “Alzheimer’s Susceptibility” Gene?

What is its function?

Which type of Alzheimer’s is it related to?

What are the most common types of mutations observed at this gene?

A
  • ApoE
  • Binds APP and effects its processing
  • Related to both types of alzheimers (typical & early onset)
  • missense amino acid mutations at sites: 112 and 158
58
Q

How does ApoE effect the risk of alzheimer’s?

A
  • DOSE DEPENDENT
  • ApoEe4 (bad type; rapidly binds APP) homozygote= 90% risk disease by 65

while heterozyogte = 45% risk

59
Q

A person’s ______ sets the range of possible _____, and the environment determines the specific _____.

A

-genotype= range of phenotype -environment determines specific phenotype

60
Q

Define population genetics:

What does the Hardy Weinburg Equation allow calculation of?

A

Population genetics: Study of the frequency of alleles in a given population + the factors that maintain or alter said alleles

Hardy Weinburg: frequency of a given genotype, using frequency of given alleles

61
Q

How is allele frequency determined (aka, p and q)?

In a population with only TWO alleles of a given gene, what is the sum of each allele’s frequenct (p+q)?

A
  • number of one allele type / total number of all alleles in population
  • If only two alleles exist, p + q always equal 1.
62
Q

What is the Hardy Weinburg equation?

(Will be given on school exam, but need to know this for boards.)

A

(p+q)^2= p^2 +2pq +q^2 = 1

….where:

p^2 is the frequency og a genotype homozygous for allele type 1

2pq is the frequency of a heterozygous genotype

and q^2 is the frequency of genotype homozygous for allele type 1

63
Q

How is population genetics applied to forensic science?

A

-Probability of a match between two DNA samples is dependent on the frequency of alleles in a given population

(population frequency subgroups may also be applied: i.e. frquency of SCA in african americans in the US)

64
Q

What is the Hardy-Weinburg LAW?

What five factors must be present to apply this law?

A

-Frequency of a genotype is based upon frequency of alleles in a given population & the frequency of genotype is constant among all generations

Requires:

  1. random mating
  2. trait present in LARGE population
  3. negligible amount of mutation
  4. negligible amount of selection
  5. negligible amount of migration
65
Q

Give an example of non-random mating that would make the Hardy-Weinburg law inapplicable:

A

-Genotype bb rarely mates due to given trait (retardation, infertility etc) –> bb will decline over time

66
Q

How does consanguineous mating effect genotype frequency over time?

A
  • Increases the number of homozygotes
  • Decreases the number of heterozygotes
67
Q

What is a stratified population?

A
  • One in which certain groups do not mate with one another
    i. e.: blacks with whites, royalty with non-royalty, Ashenkazi Jews must marry other Ashenkazi jews…
68
Q

Assortive mating is choosing a mate based on_______.

Assortive mating is similar to _______ mating.

What changes in genotype frequency are observed in assortive mating?

A
  • phenotype (intelligence, appearance, etc)
  • consanguineous
  • ^^ frequency of homozygotes
69
Q

Why must a large population be used in Hardy Weinburg genetics?

What is genetic drift?

A
  • In small populations, one genotype may be transmitted entirely by chance= easier to have “genetic drift”
  • genetic drift: establishment of a new alleles or allele frequencies
70
Q

What factor might disproportionately RAISE an allele frequency?

LOWER frequency?

In cases of increased and decreased allele frequency, what is required to maintain hardy weinburg equilibrium?

A
  • Raised by high rates of mutation
  • Lowered by low rates of MATING in a trait that reduces fitness of an individual

(If rate of mutation = rate of loss, no change in frequency, Hardy Weinburg applies)

71
Q

What is genetic fitness?

When calculating the rate of mutation in autosomal dominant disorders, what must be accounted for?

A
  • genetic fitness is the likelihood of transmitting ones genotype to the next generation
  • Autsomal dominant mutation rate must take into consideration the number of alleles lost by selection (poor genetic fitness)
72
Q

Under what circumstances can spontaneous mutation rate for AD diseases be determined?

What equations are used?

**PLEASE NOTE: THESE EQUATIONS ARE GIVEN ON THE EXAM. DO NOT MEMORIZE BUT DO BE FAMILIAR!

A
  • Only in populations that follow hardy weinburg law (rate of mutation= rate of loss of homozygote)
  • s=1-f
  • m=s x q
    where. …

s= selective disadvantage

f= fitness

m= mutation rate

q= mutant allele frequency

(He will even tell us what these variables mean. DONT MEMORIZE!)

73
Q

For XR disorders with 0 fitness, how many alleles are lost at each generation?

A

1/3 of alleles lost every generation

74
Q

A group of colonists do not have the same allele frequencies as a population they came from.

What is this called?

Why does it violate Hardy Weinburg equilibrium?

A

Founder affect

-HW equilibrium does not apply because it requires negligible amounts of MIGRATION.

75
Q

Lake Maracaibo, Venezuela has a high frequency of?

Why?

What’s the point?

A

Huntingtons; due to European founder effect

NOT IN HW EQUILIBRIUM!

76
Q

What is the HW equation for X linked traits?

A
  • females: normal- p2+ 2pq + q2 =1
  • males: simplified to p + q = 1

(no “carrier” or pq genotype, only one X chromosome present)

77
Q

How is risk determined for mendelian traits?

A

If carrier status is know: punnet square

If carrier status is NOT known: use population frequency + punnet square

78
Q

Empiric risk is the probability of ____.

How is it calculated?

A
  • recurrence
  • # affected individuals / # offspring
79
Q

GENETIC DISEASE TREATMENT TBL SESSION:

How did the treatment effectiveness of the 57 most common genetic diseases change between the years 1993 and 2008?

A
  • Large increase in “full response” 20 genetic diseases (previously 8) show full response to treatment
  • BUT Still have 17/57 with little to no response.
80
Q

GENETIC DISEASE TREATMENT TBL SESSION:

Four reasons we are unable to effectively treat genetic disease:

A
  1. pathogenesis not understood
  2. prediagnostic fetal damage
  3. severe phenotypes less treatable
  4. dominate allele affects more difficult to repair
81
Q

GENETIC DISEASE TREATMENT TBL SESSION:

Methods for treating metabolic abnormalities (5)

A
  1. avoidance of drugs / dietary restriction of nutrients
  2. replacement of substance whose synthesis is blocked (thyroid hormone)
  3. Diversion: achieve task by alternative metabolic path (urea cycle disease)
  4. Enzyme or Receptor inhibition
  5. Depletion
82
Q

GENETIC DISEASE TREATMENT TBL SESSION:

Many metabolic diseases result from failure to synthesize a product and subsequent precursor buildup. What is the prototypical disease of this type?

A

-PKU, cannot synthesize tyrosine, phenylalanine buildsup –> phenylketones form = motor and mental retardation + musty odor

83
Q

GENETIC DISEASE TREATMENT TBL SESSION:

In PKU, why do abnormalities present AFTER birth?

In addition to protein, what subtrates are ultimately products of Phe?

Where is PAH normally found?

A
  • Maternal PAH is protective in utero
  • DOPA, melanin, neurotransmitters
  • PAH mostly in liver, some in kidney
84
Q

GENETIC DISEASE TREATMENT TBL SESSION:

What are the three pathways for Phe degradation?

A
  1. Phe –> tyrosine –> fumarate + acetoacetate
  2. Phe –> phenylpyruvic acid (1-transamination)
  3. Phe–> Phenylethylamine (decarboxylation)
85
Q

GENETIC DISEASE TREATMENT TBL SESSION:

Describe how diversion is used to treat urea cycle disorders

A

GIVE BENZOATE SUPPLEMENTS:

NH3 –> Glycine

Gylcine combines with benzoate supplement –> hippurate

Hippurate excreted in urine

(Nitrogenous waste excreted via alternative path!= DIVERSION.)

86
Q

GENETIC DISEASE TREATMENT TBL SESSION:

Compare and contrast Hemophilia A and B

A
  • XR, both clotting deficiencies
  • A: factor 8 missing (most common)
  • B: factor 9 missing
87
Q

GENETIC DISEASE TREATMENT TBL SESSION:

Describe the dangers assc with giving purified clotting factors to treat hemophilia.

Describe potential benefits of treating with recombinant factor proteins.

A
  • Purified blood products: ^^ cost, ^^ injections, ^^ infection risk, arthritis risk
  • Recombinant proteins: cheaper, less injections, less infection risk
88
Q

GENETIC DISEASE TREATMENT TBL SESSION:

What is “Z variant PI”?

A
  • anormal a1 anti-trypsin (protease inhibitor- “PI”)
  • does NOT effectively inhibit elastase
  • builds up in hepatocyte ER
  • causes emphysema + cirrhosis

(^^ risk in smokers due to oxidaxtion of a met residue on PI)

89
Q

GENETIC DISEASE TREATMENT TBL SESSION:

What three diseases are successfully treated with somatic gene transplant?

What are two methods for somatic gene transplantation?

A
  • Gaucher’s, Hunter’s, Hurler’s (Lysosomal Storage Diseases)
  • administer allogenic marrow cells
  • Transduce PT’s bone marrow cells with wild type gene
90
Q

GENETIC DISEASE TREATMENT TBL SESSION:

Problem with germline gene therapy

A
  • Can be used to alleviate disease suffering but also for eugenic purposes
  • ETHICAL/ MORAL DEBATE.
91
Q

GENETIC DISEASE TREATMENT TBL SESSION:

Major difference between somatic and germline gene therapy?

A

-In somatic therapy, transduced trait cannot be passed on to progeny.

(No potential for eugenics)

92
Q

GENETIC DISEASE TREATMENT TBL SESSION:

Compare/ contrast en vivo and ex vivo gene therapy.

What is an example of en vivo gene therapy?

A
  • en vivo: vector targeted to a tissue transfects cell in body
    (i. e. viral vector targeted to liver in FIX treatment and in treatment of hypercholesterolemia)
  • ex vivo: patient’s cells taken out, transfected in culture, reintroduced
93
Q

GENETIC DISEASE TREATMENT TBL SESSION:

Initial diseases chosen for gene therapy due to relative ease of gene replacement?

Why are dominant disorders harder to treat than recessive?

A
  • diseases involing ONE gene and ONE organ
  • in recessive disease, defective protein replacement is sufficient for treatment.
  • in dominant disease, defective protein must be both REMOVED and REPLACED.
94
Q

GENETIC DISEASE TREATMENT TBL SESSION:

-Constituitive vs Regulated Disease:

which is easier to treat?

A

-Consituitive genes are more easy to replace than those than have strict transcriptional regulation

95
Q

GENETIC DISEASE TREATMENT TBL SESSION:

Why is there interest in new F.IX replacement therapy?

A
  • inconvenience of frequent injections of purified clotting factors, risk of deleterious immune responses against the therapeutic protein & infection
  • Purified proteins also ^^ $$$.
96
Q

GENETIC DISEASE TREATMENT TBL SESSION:

Which vectors have been used in FIX gene therapy and what were the preferred target tissues.?

A
  • adenovirus
  • adeno assc virus (AAV)
  • lentivirus
  • muscle and liver both targeted; liver = better outcome
97
Q

GENETIC DISEASE TREATMENT TBL SESSION:

Why is liver the preferred target for F. IX gene therapy?

A
  • FIX is naturally produced in the liver
  • Hepatocytes have more efficient secretion machinery than myocytes
  • The liver-directed gene transfer prevents subsequent antibody and CD8+ T cell responses
98
Q

GENETIC DISEASE TREATMENT TBL:

What are the immune responses encountered for injected (in vivo) adenovirus and AAV gene therapy vectors? (3)

Differences between Adenoviral and AAV vectors?

A
  1. antibody binding and elimination of the vector particles
  2. direct stimulation of innate immunity pathways by vector particles
  3. cell-mediated adaptive immunity can be responsible for the elimination of vector transduced cells

AAV vectors = LEAST immune activation!!!

99
Q

GENETIC DISEASE TREATMENT TBL:

Why is F. IX a candidate for gene therapy?

A
  • phenotype is attributable to the lack of a single protein
  • gene is small and easily inserted into vectors

DT4- Exam 3 (14 decks)

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