M1-C1-L43 --> Non Traditional Inheritance

Front 1

What are the three ways that mitochondrial genetics differs from mendelian genetics?

Back 1

1.) Heteroplasmy / Threshold Effect
2.) Maternal Inheritance
3.) Mitotic Segregation

Hint 1

Things that make you go HMM...

Front 2

Intercellular and intergenerational mtDNA transmission follows what principle?

Back 2

Principle of population genetics.

Hint 2

STFU Young. You don't need a hint for this one.

Front 3

Why do children of heteroplasmy mothers have widely varying proportions of mtDNA genotypes?

Back 3

Due to random partitioning of mitochondria during expansion of oogonial population.

Hint 3

How does mitochondria (not mtDNA) segregate in oogenesis?

Front 4

Define Homoplasmy

Back 4

The presence of one type of mtDNA in each cell

Hint 4

"Homo" and "plasmy"

Front 5

Define Heteroplasmy

Back 5

The presence of more than one genetically distince mtDNA in each cell.

Hint 5

"Hetero" and "plasmy"

Front 6

For all mtDNA mutations, the clinical expressions are dependent on what three factors?

Back 6

1.) Heteroplasmy
2.) Threshold Effect
3.) Tissue Distribution

Hint 6

HTT

Front 7

How does heteroplasmy effect clinical expression?

Back 7

Based on the abundance of mutant mtDNA

Hint 7

Ratio

Front 8

How does the Threshold Effect factor in to clinical expression?

Back 8

Based on the vulnerability of each tissue to impaired oxidative metabolism

Hint 8

OX

Front 9

How does tissue distribution affect the clinical expression?

Back 9

Based on the distribution of mutant mtDNA in tissue.

Hint 9

?

Front 10

asdfsaf

Back 10

asfd

Hint 10

afdasf

Front 11

1.) Fertilization
2.) Decrease in mtDNA copy number per cell
3.) Primordial germ cells
4.) Low intercellular variance
5.) Segregation
6.) Primary oocytes
7.) High intercellular variance
8.) Oocyte maturation
9.) mtDNA amplification
10.) Mature Oocyte

Back 11

_

Hint 11

Should be obvious

Front 12

Tissues most dependent (most affected) by OXPHOS function. X 4

Back 12

CNS, Muscle, Vision, and Hearing.

Front 13

Give an example of a pleiotropy mutation?

Back 13

A3243G mutation on the tRNA-leu gene.

Front 14

Give four variable expressions for the pleiotropic mutation of A3243G mutation on the tRNA-leu gene.

Back 14

1.) MELAS (Mitochondrial Encephelomyopathy with Lactic Acidosis and Stroke episodes)
2.) Diabetes / Deafness
3.) CPEO (Chronic Progressive External Opthalmoplegia)
4.) Cardiomyopathy

Front 15

Give an example of three overlapping phenotypes resulting from a mtDNA deletion mutation.

Back 15

1.) Kearns/Sayres Syndrome
2.) Pearson Syndrom
3.) PEO (Progressive External Opthalmoplegia)

Hint 15

Kiss the pear and pee it out.

Front 16

Mitochondrial DNA deletions occur how?

Back 16

de novo

Hint 16

latin

Front 17

Define nondisjunction

Back 17

Failure of homologous chromosomes (meiosis I / mitosis) or sister chromatids (meiosis II) to properly separate in to different progeny cells.

Front 18

Define uniparental disomy (UPD)

Back 18

Disomic cell line containing two chromosomes of a given kind from only one parent

Front 19

Two types of uniparental disomy (UPD)

Back 19

1.) Isodisomy
2.) Heterodisomy

Front 20

Define Isodisomy

Back 20

Two of the same (homolog) chromosomes present in a cell line

Front 21

Define Heterodisomy

Back 21

Two, different chromosomes present from only one parent in a cell line

Front 22

List four possible causes of disease seen with UPD.

Back 22

1.) AR disorder from one document parent carrier
2.) X-linked disorder transmitted from father to son (paternal heterodisomy)
3.) X-linked disorder expressed from father to daughter in homozygous form (paternal isodisomy)
4.) Involving genetic imprinting.

Front 23

1.) Chromosomes fail to separate to daughter cells
2.) Meiosis I (Drama!)
3.) Meiosis II (No drama)
4.) Biparental inheritance
5.) Biparental inheritance
6.) Uniparental heterodisomy
7.) Uniparental isodisomy resulting from chromosome duplication.

Back 23

Nondisjunction in Meiosis I

Front 24

1.) Meiosis I
2.) Meiosis II
3.) Chromosomes fail to separate properly to daughter cells
4.) Biparental inheritance
5.) Biparental inheritance
6.) Uniparental isodisomy
7.) Uniparental isodisomy resulting from chrosome duplication

Back 24

Nondisjunction in Meiosis II

Front 25

Define Genetic imprinting

Back 25

Parent of Origin specific silencing of a subset of mammalian genes

Front 26

Define epigenetic

Back 26

A set of reversible heritable gene function that occur without a change in the DNA sequence.

Front 27

What type of phenomenon is imprinting?

Back 27

Epigenetic

Front 28

Imprinting involves what two mechanisms?

Back 28

1.) Allele specific methylation AND/OR
2.) Histone modification and alteration of chromatin structure.

Front 29

When are imprints "erased?"

Back 29

In between generations where new imprints established based on gender of germ line.

Front 30

T/F - Is genetic imprinting tissue specific?

Back 30

T - Imprinting occurs in some tissues and biallelic in others.

Front 31

When is genetic imprinting regulated?

Back 31

Regulated early during embryonic development, but biallelic in adults.

Front 32

When are imprinted genes expressed?

Back 32

Expressed during embryo and placenta development, as well as prenatal and postnatal brain.

Front 33

With the occurence of imprinted genes, paternally expressed genes promote what?

Back 33

Growth

Front 34

With the occurence of imprinted genes, maternally expressed genes promote what?

Back 34

Growth regulation

Front 35

List the 5 paternally expressed (maternally imprinted) genes on 15q-11-q13

Back 35

1.) ZNF127
2.) IPW
3.) NDN
4.) SNURP / SNRPN
5.) MAGEL2

Hint 35

After drinking zinfadel, I pee with an indian, snurp snurpin, and magel too.

Front 36

List the maternally expressed (paternally imprinted) gene on 15q-11-q13

Back 36

UBE3A

Hint 36

Women, you be 3 assholes

Front 37

A deletion in what gene causes either PW or AS

Back 37

15q-11-q13

Front 38

What genetic cause is the most common cause of Prader-Willi?

Back 38

Paternally deleted genes on 15q-11-q13

Front 39

What genetic cause is the most common cause of Angelman Syndrome?

Back 39

Maternally deleted genes on 15q-11-q13

Front 40

How can UPD play a role in Prader-Willi

Back 40

A patient can have PW if they obtained both pairs of the chromosome maternally

Front 41

How can UPD play a role in Angelman's Syndrome

Back 41

A patient can have AS if they obtained both pairs of the chromosome paternally

Front 42

Dynamic mutations defined

Back 42

A mechanism of a mutation that is caused by the expansion of a repeated sequence in novel genes

Front 43

Common Trinucleotide Repeat Expansion Mutations X 2

Back 43

1.) CAG
2.) CGG

Front 44

Trinucleotide Repeat Expansion mutations are usually found in which part of the gene (general)? X 2

Back 44

1.) In genes that regulate transcription factors
2.) In genes that regulate development

Front 45

What can be anticipated in trinucleotide repeat expansion mutations during successive generations? X 3

Back 45

1.) Earlier onset of disease.
2.) Increasing severity.
3.) Increasing length of repeats

Front 46

In what type of diseases do trinucleotide repeats expand with paternal transmission?

Back 46

CAG repeat diseases (Type I)

Front 47

In what type of diseases do you see expansion of trinucleotide repeats associated with maternal transmission?

Back 47

1.) Fragile X Syndrome (CGG)
2.) Myotonic dystrophy (CTG)
3.) Friedreich Ataxia (GAA)

Front 48

Where do you find Type I trinucleotide repeat expansion mutations?

Back 48

Coding regions

Front 49

Where do you find Type II trinucleotide repeat expansion mutations?

Back 49

Noncoding regions

Front 50

Type I trinucleotide repeat expansion mutations have what type of molecular and genetic character?

Back 50

Genetic: CAG mutation in coding region
Molecular: Mutant protein usually has long polyglutamine tracts.

Front 51

Symptoms of Type I trinucleotide repeat expansion mutations.

Back 51

Neurodegenerative disorder with neuronal loss in brain, brainstem, and spinal cord.

Front 52

Define Gain of Function mutation and where it is usually seen in?

Back 52

Mutation on gene creates new gene product that has a new and abnormal function.

Type I trinucleotide repeat expansion disorder
Seen in Type I trinucleotide repeat expansion mutation

Front 53

What type of transmission is usually seen in Type I trinucleotide repeat expansion mutation

Back 53

Autosomal Dominant except for SBMA (Spinobulbar muscular atrophy which is X-linked.

Front 54

When do you see the greatest expansion in Type I trinucleotide repeat expansion mutation?

Back 54

Father to daughter transmission.

Front 55

Huntington Disease is what type of disorder?

Back 55

Trinucleotide Repeat Expansion Type I

Front 56

Genetically, what causes Huntington's Disease?
(type of repeat and chromosome #)

Back 56

CAG repeats on Chromosome 4

Front 57

What kind of transmission type is Huntington's?

Back 57

Autosomal Dominant

Front 58

What can be said about the mutation rate of Huntington's?

Back 58

One of the lowest mutation rates in humans.

Front 59

Symptoms of Type II Trinucleotide Repeat Expansion.

Back 59

Variety of clinical features other than neurodegeneration.

Front 60

Penetrance of Fragile X syndrome.

Back 60

Males: 80%
Females: 30%

Front 61

Inheritance character of fragile X with mental retardation.

Back 61

Single most common inherited cause of mental retardation

Front 62

Uniqueness of female transmitted Fragile X syndrome.

Back 62

Only time when permutation can become full blown mutations

Front 63

Where can we find the location of the Fragile X Syndrome gene?

Back 63

FMR1 (on the distal end of Xq) has CGG repeats in the 5' end of the untranslated gene.

Front 64

T/F - Is mental retardation associated with Fragile X permutation

Back 64

NO.

Front 65

What magnitude of repeats exist in the permutation state of Fragile X syndrome

Back 65

59-200 CGG repeats

Front 66

Unique character of male transmittance in Fragile X.

Back 66

Males can not transfer to daughters, but those daughters can have affected sons.

Front 67

Mechanism leading to Trinucleotide Repeat Expansion

Back 67

Mechanism uncertain, but believed that slipped mispairing mediated by repeats during DNA synthesis causes extra repeats

Front 68

Describe a mechanism used to maintain repeat integrity against trinucleotide repeat expansion disorders.

Back 68

In FMR1 alleles, the AGG triplet interrupts the CGG region every 9-10 repeats, thus preventing slippage.

Front 69

LHON stands for what?

Back 69

Leber Hereditary Optic Neuropathy

Front 70

What magnitude, type, and nature of mtDNA mutations cause LHON.

Back 70

18 missense mutations of the homoplasmic kind in mitochondrial DNA.

Front 71

How many primary location sites for mutatations can be attributed to LHON?

Back 71

90% of those affected have mutations on three sites.

Front 72

Describe the mutational load of LHON.

Back 72

Mitochondrial, leukocyte mutational load over 75% leads to affected individuals.

Front 73

Penetrance of LHON.

Back 73

Males 40%
Females 10%

Front 74

What does MERRF stand for?

Back 74

mitochondrial Myopathic myclonic Epilepsy Ragged Red Fiber on muscle biopsy

Front 75

Where does the mutation for MERRF occur?

Back 75

On the mitochondrial tRNA-lys gene

Front 76

How many places of mutations are associated with MERRF?

Back 76

90% of affecteds have mutations on four gene locations.

Front 77

What type of mitochondrial genetics exist in MERRF patients?

Back 77

Heteroplasmic with variable expression.

Front 78

What type of stains are exhibited in MERRF and what does each show?

Back 78

1.) Modified Gomori trichrome stain - shows ragged red fibers.
2.) Cytochrome Oxidase stain - shows lack of cytochrome oxidase in muscle fiber.

Front 79

In what tissues can we find mutations for MERRF typically?

Back 79

All of them especially the WBC

Front 80

Individuals with a few symptoms of MERRF or asymptomatic maternal relatives show what degree of mutation?

Back 80

Undetectable mutation in mtDNA from leukocytes, but detectable in other tissues.

Front 81

Critical factors that affect MERRF children X 2.

Back 81

1.) Mutational load
2.) Tissue distribution

Front 82

MERRF recurrence risk in males and females.

Back 82

Males: cannot pass it
Females: can pass it to all children

Front 83

Describe the treatments of mitochondrial disorders.

Back 83

1.) Supportive
2.) Coenzyme Q10/ldebenone
3.) Riboflavin

Front 84

Describe the benefits of Coenzyme Q10/ldebenone in mitochondrial disorder

Back 84

Subjective benefits.
1.) Bypass block with artificial electron acceptor
2.) Minimize free radical damage.

Front 85

Describe the benefits of Riboflavin in mitochondrial disorder.

Back 85

Enhances residual activity in Complex I and Complex II deficiency.