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Genetics Of Complex Disease > Mitochondria Disease > Flashcards

Mitochondria Disease Flashcards

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1
Q

Give some mt functions

A

Produce atp from tca cycle and oxphos

Fe clusters as catalytic units eg in etc

Buffer ic calcium eg in muscles and neurones

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2
Q

What do they convert into atp

A

Fa and glucose

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3
Q

Where are the 5 multimeric protein complexes located

A

Inner membrane

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4
Q

What else other than the 5 complexes needed for atp gen

A

2 electron carriers ubiquinone and cytochrome c

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5
Q

Where are the electrons transferring down chain from

A

Reduced FAD and NADH (the h ions)

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6
Q

What does this allow

A

Protons to be pumped from matrix to intermembrane space and then down complex v (ATPase)

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7
Q

What does the mt dna look like

A

Circular
Intronless
13 peptides encoded
22 trna
2 RRNA (ribosomes)

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8
Q

Which complex has most genes encoded by mt

A

Complex 1

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9
Q

Which complex doesn’t have any subunits encoded by mt

A

II (succinate dehydrogenase)

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10
Q

Which complex 1 gene encodes by light strand (most genes are in heavy strand)

A

Mt-ND6

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11
Q

Why is it important trnas flank protein coding genes

A

Txn of the strands occurs all at once since no introns, so long messengers need to be processed and read correctly

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12
Q

What stops elongation of txn and is mutated in MELAS commonly

A

mTERF

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13
Q

Which non coding region does txn and replication of Mtdna start

A

D-loop

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14
Q

What is the promoter in d-loop for light strand txn

A

Light strand polycistron

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15
Q

H strand has 2 promoters. What is hsp1 for

A

Rrna encoding (ribosomes) and the first trna (leucine)

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16
Q

What does trna leu form

A

Clover lead

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17
Q

What is the other hsp for

A

Entire h strand txn

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18
Q

What txn activator needed by mt to bind to rna polymerase for txn activation

A

TFAM

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19
Q

How is mt inherited

A

Maternally, oocytes have 100,000 copies of mt dna

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20
Q

How can migration be tracked by mtdna

A

Overtime developed polymorphisms segregated through haplogroups

Each ethnic group can be indentfied by haplogroup segregation

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21
Q

What is the term for cells which only have wt mtdna xopies

A

Homoplasmic wt

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22
Q

What does heteroplasmy mean

A

Cells have a mix of mutant mtdna and wt xopies

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23
Q

What is the biochemical threshold

A

The threshold of exceeded by too high hereroplasmy %, the wt can’t compensate for the loss of activity by mutant copies = cell dysfunctionb

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24
Q

Which types of tissues likely have a lower threshold for hereroplasmy dysfunction

A

Those largely dependant on oxidative metabolism. Eg brain, retina, skeletal muscle

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25
Q

Which complex is used to compare other deficiencies eg cox/complex Iv deficiency

A

Complex II bc not mt encoded

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26
Q

Why would staining patterns show cells both blue and brown stained in a muscle

A

Cells blue might have less functional cox because higher hereroplasmy/mutation, others might have lower heteroplasmy so more cox functional

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27
Q

How can diff tissue types/ cells in a tissue have different heteroplasmy

A

Because of random segregation of mt during mitosis of cells in dividing tissues

28
Q

What is a genetic bottleneck referring to in mtdna

A

PGCs segregate their mtdna copies so each oocyte only gets a few copies which are used to repopulate so oocyte has throuaands of copies

29
Q

How does this process mean genetic inheritance of mt disease is hard to detect

A

Because segregation of mt dna xopies is random and depends on which oocyte is fertilised to then make the embryo deciding if more heteroplasmy or less

30
Q

How many mt proteins does the nucleus encode

A

1100 around

31
Q

What sorts of proteins are these

A

For nucleotide synthesis,for replication, for txn, translation, protein import, other oxphos subunits

32
Q

What pattern of inheritance do nuclear genes follow

A

Mendelian (ie ar or ad)

33
Q

What things for replication does nyckeus encode

A

Poly-gamma and twinkle helicase

34
Q

Can nuclear gene mutations cause mt disease

A

Yes!! Eg polG , rrm2b

35
Q

What does rrm2b do which is commonly mutated in mt diseases

A

Encodes a subunit of a ribonucleotide reductase which helps synthesise nucleotides for more mtdna synthesis

36
Q

Why is replication of mtdna so important

A

Because mutational rate is so quick, it is essential to maintain functional dna

37
Q

What is the term for the gradual increase/changes in heteroplasmy bc of unequal division or replication of mutant

A

Clonal expansion

38
Q

How does it happen in non dividing/post mitotic tissues like neurones

A

The mtdna replicate /still being turned over bc of ros

39
Q

Why do single large scale deletions allow faster replication

A

Smaller mtdna genome

40
Q

What does this cause overtime

A

Increased cell heteroplasmy as faster mutant replication

41
Q

Why would heteroplasmy never go beyond 90% or slowly heteroplasmy decreases

A

Would die

Selected against and die out overtime

42
Q

What type of other mutation is there

A

Point mutation

43
Q

What % of point mutations are inherited

A

75%, some are somatic

44
Q

Even if 75% inherited, why is it hard to predict child

A

Mothers mutations may not have reached threshold

45
Q

Explain the clinical heterogeneity of mt related syndromes

A

Different ages onset of symptoms and different severities due to different heteroplasmy levels

46
Q

Which syndrome with 3 mutations is most common

A

Lhon

47
Q

What is the most common point mutation

A

A>G3243

In mttl1 gene (trna leu)

48
Q

What are the lhon mutations in

A

ND1,4 and 6 (complex 1)

49
Q

What ndna mutations most common

A

Twinkle/PEO1, polG, rrbm2b

50
Q

What is ptosis which is a neurological symptom

A

Droopy eyes

51
Q

What is LHON

A

Bilateral vision loss due to retinal ganglion cells loss

52
Q

What causes loss of rgcs

A

Increased ros and reduced oxphos

53
Q

Does it have full penentrance

A

No

54
Q

What % heteroplasmy needed for symptoms

A

76%

55
Q

What haplotype were vision loss more likely

A

J

56
Q

Why is it suggested a complex disease

A

Found nuclear gene snps increasing risk and also environment like smoking affect rgc survical

57
Q

What is inefficient when mttl1 mutated

A

Translation

58
Q

Why is complex 1 deficiency common in mttl1 mutant

A

Many genes encoded on the mtdna

59
Q

What other syndromes seen in mttl1 mutant

A

Melas
Maternally inherited diabetes and deafness
Cpeo

60
Q

Which syndrome associated with mttl1 needs a higher heteroplasmy to be seen

A

Melas (50-92%)

61
Q

Single large scale deletions occur, what other deletion

A

Multiple deletions

62
Q

How

A

Mutation in nuclear dna which affects mtdna maintenance/stability everytime it replicates

63
Q

What are the 3 syndromes caused by the single large scale deletions

A

Pearsons,cpeo,kss

64
Q

Why does kss have a later onset

A

Due to clonal expansion overtime occurring to reach threshold

65
Q

What dominance pattern is multiple deletion syndromes

A

Ad or ar in the nuclear genes for maintenance eg twinkle, polg, rmtb2

66
Q

How can you prevent mt disease passed into offspring

A

Prenatal screening
Egg donor
Preimplantation diagnosis (do ivf and look at heteroplasmy of embryo before implanted)
Mt donation

67
Q

What 2 types of mt donation are there

A

Maternal spindle transfer

Pro nuclear transfer

Genetics Of Complex Disease (17 decks)

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