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GGE > Genetics 4 - Mitochondria > Flashcards

Genetics 4 - Mitochondria Flashcards

1
Q

learning outcomes

A
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2
Q

what is a mitochondrion

functions

genome

how did it originate

A

double membrane-bound organelle found in most eukaryotes

powerhouse of the cell - generate ATP

also involved in cell signalling

growth

death

cell cycle regulation

has independent (of nuclear DNA) circular genome

thought to have originated as free living bacteria which were taken up by eukaryotes to carry out ox phos (endosymbiotic theory)

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3
Q

no of mito. in nucleated cells

A

500-2000

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4
Q

cone cell photoreceptor of the eye - proportion of mito.

also muscles of eye

heart

A

mito. make up 80% of IC volume

60% - lateral rectus and other extra-ocular muscles

40% - heart

high proportion in energy dependent cells e.g. CNS, brain, eye, heart

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5
Q

human vs mitochondrial genome

  1. carriers of DNA
  2. sequences responsible for
  3. no of copies per cell
A

NUCLEAR GENOME

c. 23000 protein coding genes, 3200 Mb - million bps

23 de linear chromosomes (50-260 Mb each)

1.5% is protein coding sequences

non-functional gene related sequences (pseudogenes and gene fragments)

MITOCHONDRIAL GENOME

37 genes, 16.6 Mb

circular dsDNA (linear forms exist)

16569 bp (93% coding mRNA or tRNA or rRNA) - efficient

dozens of copies per mito. and 1000s of this genome/cell

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6
Q

mtDNA sequence

A

Cambridge sequence

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7
Q

no of genes of mito. genome

proportion that code for non mRNA

A

37 genes total

24 encode for non mRNA

22 mitochondrial tRNA (white)

1 mitochondrial 23S rRNA (blue)

1 mitochondrial 16S rRNA (blue)

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8
Q

no of genes transcribed and translated to proteins on mt ribosomes

what are they related to

A

13

all related to ox phos

7 NADH dehydrogenase subunits (ND - yellow) I

3 cytochrome C oxidase (COX - orange) IV

2 ATPase (ATP - red) V

1 cytochrome B (CYTB - peach) III

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9
Q

I

A

NADH dehydrogenase subunits

7 present

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10
Q

IV

A

cytochrome C oxidase

3 present

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11
Q

V

A

ATPase

2 present

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12
Q

III

A

cytochrome B

1 present

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13
Q

electron transport chain and ox phos

A

5 protein complexes

Pass protons along to create proton conc gradient

Protons pumped into space between inner and outer membranes

ATP produced

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14
Q

ROS generation and ATP synthase

A

ROS are generated during ATP synthesis

rate of O2 consumption has to correspond to rate of ATP synthesis so that ROS are neutralised

uncoupling of generation and consumption leads to accumulation of ROS - O2 ions and peroxides which are toxic

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15
Q

ROS uncoupling and accumulation

A

may occur in some mito. diseases especially if person has a fever

ROS accumulation ⇒ oxidative damage (including to mtDNA)

may trigger apoptosis

CNS may be particularly vulnerable to this

infection may trigger neurological problems in patients with mt disease

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16
Q

no of gene products needed to make a mitochondrion

where are mito. proteins encoded

A

3000 gene products to make a mito.

most mito. proteins are encoded on nuclear genome (transferred from mito. genome over evolutionary time) and synthesised in cytoplasm

therefore most inherited disorders of mito. are related to changes in nuclear DNA rather than mtDNA

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17
Q

no of mito. gene products needed to make ATP

A

13 - mtDNA

77 - nuclear genome

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18
Q

what remaining mito. gene products do

A

signalling molecules involved in regulation of:

MP

cell cycle control

development

apoptosis

cellular metabolism

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19
Q

how is mitochondrial DNA inherited

A

almost exclusively along maternal line

fertilised oocyte degrades mtDNA carried by sperm

mothers transmit mtDNA to sons and daughters

only daughters can transmit their mtDNA to the next generation

sons can inherit mtDNA disease but can not transmit

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20
Q

mtDNA sequence variation

A

mtDNA of any individual shows variation from Cambridge Consensus Sequence

most variation is silent polymorphisms

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21
Q

region on mtDNA - useful for forensic purposes

A

Control Region

highly polymorphic

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22
Q

mtDNA copies per cell

replication and cell cycle

A

100s-1000s of mtDNA copies per cell

variable - replication not coordinated with cell cycle

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23
Q

mtDNA vs genomic DNA - variation

A

reduced stringency of proofreading and replication error correction with mtDNA

no mtDNA repair mechanism

many fold higher sequence variation than genomic DNA

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24
Q

homoplasmy

A

all mtDNA sequences are the same

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25
Q

heteroplasmy

A

variation in mtDNA sequences (common)

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26
Q

intercellular heteroplasmy

A

variation between cells

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27
Q

intracellular heteroplasmy

A

variation within cells

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28
Q

what represents the only source of mtDNA genetic diversity

A

mutation

as mitochondria do not undergo recombination during cell division

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29
Q

if an individual has a mtDNA mutation associated with a dysfunctional allele product, what does it mean for their daughter cells and somatic cells

A

proportion of mtDNA sequences in each cell/tissue that carries the dysfunctional allele may vary

during cell division random segregation of mito. (and mtDNA) between 2 daughter cells occurs

however mtDNA mutations in somatic cells are not heritable

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30
Q

mitochondrial heteroplasmy and threshold effect

A

phentoypically affected daughter cells are the ones that end up with more mito. with mutated DNA

Incomplete penetrance

Variable expressivity

Pliotrophy - 1 gene can influence 2 or more seemingly unrelated phenotypic traits

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31
Q

pliotrophy

A

1 gene can influence 2 or more seemingly unrelated phenotypic traits

32
Q

how can oocytes vary

A

different oocytes from one woman may vary in the extent of heteroplasmy

some may get a high proportion of pathogenic mtDNA - genetic bottleneck

predicting phenotype from genotype and genetic counselling

33
Q

what does phenotype depend on

A

proportion of pathogenic mtDNA in tissues of each family member

highly variable

34
Q

hallmark of disease associated with mtDNA

A

identical mtDNA mutations may be associated with different manifestations

can also happen that very similar manifestations arise from different mutations

35
Q

what is mitochondrial disease often associated with

systems involved

A

multi-organ degenerative disease

especially high energy organ systems

CNS

muscle (skeletal and heart)

liver

kidney

36
Q

things to remember

A
37
Q

learning outcomes

A
38
Q

retina of a patient with LHON

A
39
Q

Leber Hereditary Optic Neuropathy

A

bilateral, painless, subacute visual failure that develops during young adult life

males are 4x more likely to be affected than females

40
Q

symptoms of LHON

A

entirely asymptomatic until onset in 1 eye

similar symtpoms appear in other eye an average of 8 weeks later

in 25% of cases, visual loss is bilateral at onset

small % of cases, central vision gradually improves but recovery is incomplete

for most central vision loss is profound and permanent

some individuals with LHON, usually women, may also have MS like illness - LHON plus

41
Q

type of mutation - LHON

A

point mutation

42
Q

LHON severe phenotype, with little chance of recovery mutation

A

m.3460G>A in MT-ND1

43
Q

most common (Asians/Caucasians) LHON mutation

A

m.11778G>A in MT-ND4

44
Q

mutation associated with LHON in French Canadians

mild, with best long-term prognosis

A

m.14484T>C in MT-ND6

FOUNDER EFFECT = Small population that interbreed ⇒ Higher incidence of particular allele

45
Q

LHON heteroplasmy

A

(difference in mito. sequence in DNA =) heteroplasmy in polymorphonuclear leukocytes occurs in circa 10-15% of those with a pathogenic LHON causing mtDNA sequence

individuals with a m.11778G>A pathogenic variant load of <75% in their leukocytes may be unaffected

heteroplasmy in cone cells may influence risk of developing visual impairment

in general heteroplasmy of < 75% pathogenic variant load is rare

majority of LHON carriers are homoplasmic

46
Q

nature of mtDNA - majority of LHON carriers

A

homoplasmic

47
Q

LHON management

A

avoid smoking

limit alcohol use

avoid other environmental toxins

diet

48
Q

LHON genetic counselling

A

gender and age dependent penetrance - 50 (av age of onset)

mother of a proband usually has the mtDNA mutation and may or may not have symptoms

up to 40% of cases = SIMPLEX - occur in a single individual in a family

49
Q

transmission of LHON - males vs females

A

a male (affected or unaffected) with a primary LHON-causing mtDAN mutation cannot transmit the mutation to any of his offspring

a female (affected or unaffected) with a primary LHON-causing mtDNA mutation transmits the mutation to all of her offspring but to varying degrees (heteroplasmy) -

Depends on proportion of mutated mtDNA that ends up in the ova that make the child - Also environmental factors - THRESHOLD EFFECT

50
Q

prenatal diagnosis of LHON

A

mtDNA mutational load in amniocytes and chorionic villi is unlikely to correspond to that of other foetal or adult tissues

presence of mtDNA mutation does not reliably predict the occurence, age of onset, severity, or rate of disease progression

51
Q

penetrance of LHON

A

50% of males, 10% of females who harbour a primary LHON causing mtDNA mutation become affected

a compensatory mechanism of activated mitochondrial biogenesis and increased mtDNA copy number may explain why some carriers are unaffected

promoted by oestrogens in females, which amy partially explain the gender bias

52
Q
A

true

affected person is more likely to homoplasmic than a non-affected person

53
Q
A

males with mtDNA mutation 4x more likely to manifest LHON than females with the same mtDNA mutation

54
Q

haplogroups

A

describes individual branches, or closely related groups of branches, on the genetic family tree of all humans

all members of a haplogroup can trace their ancestry back to a single individual

haplogroups arose through mutation and migration

55
Q

mtDNA haplogroups

A

mtDNA sequence polymorphism variations that have occurred over more than 150,000 years and correlate with the geographic origins of populations traced through maternal lineages

56
Q

daughters of cinderella

A
57
Q

what mutation is possible for LHON, and is in fact common with mtDNA

A

de novo mutation

58
Q

how to group individuals that appear to have a more/less recent common ancestor

A

by aligning mtDNA sequences

members of a haplogroup have a MRCA

subclades within haplogroups with an even MRCA

59
Q

members of an mtDNA haplogroup - mtDNA

A

members of an mtDNA haplogroup have more similar total mtDNA to other members of the same haplogroup

have similar mutations/polymorphisms in other mtDNA genes

as most mtDNA codes for proteins, mito. polymorphisms can influence energy metabolism and contribute to the expression of the overall clinical phenotype

60
Q

mitochondrial haplogroups and LHON - higher risk of LHON with what haplogroups

A
61
Q

Parkinson’s - associated haplogroups

A

higher incidence among mtDNA haplogroups H but lower for J and K

62
Q

protection from sepsis

A

H haplogroup

63
Q

increased longevity

A

I

J

T

64
Q

uquivalent haplogroup for male line

A

Y chromosome

EXCEPT FOR pseudoautosomal region

65
Q

is mtDNA inheritance exclusively matrilineal

A

the central dogma of maternal inheritance of mtDNA remains valid

there are some exceptional cases where paternal mtDNA could be passed to the offspring

66
Q

Leigh Syndrome

mortality

A

progressive neurometabolic disorder

50% mortality per year from diagnosis

67
Q

characterisations of Leigh Syndrome

A

mito. dysfunction caused by hereditary genetic defect

MRI necrotising lesions in the midbrain and brainstem

bilateral symmetrical degeneration of the brainstem, cerebellum and basal ganglia

typical onset in infancy or childhood, often after a viral infection (metabolic challenge)

may begin later

1 in 40,000 births

68
Q

clinical manifestations of Leigh Syndrome

A

elevated lactic acid (blood and CSF)

bilateral lesions in the thalami, posterior parietal and temporal lobes

positive on metabolic screening

cough, cold, fever, difficulty breathing

seizures

slow to obtain developmental milestones

dysarthria

dysphagia

hypertonic and involuntary movements

palpable liver of 2cm below costal margin

69
Q

Leigh-like Syndrome

A

criteria for LS only partially met despite overall clinical picture indicative of LS

often peripheral nervous system involvement, including polyneuropathy or myopathy

often non-neurological abnormalities - dysmorphic features, cardiac, endocrine and GI

resp impairment due to brainstem involvement usually absent

70
Q

genetic heterogeneity of Leigh Syndrome

A

mutations in at least 75 genes

mito. disorder with broadest genetic (and clinical) heterogeneity

pyruvate dehydrogenase (PDHC) deficiency (citric acid cycle)

resp chain enzyme defects - complexes I, II, IV and V (ox phos)

NARP mutation

MERRF mutation

71
Q

4 different patterns of inheritance for Leigh Syndrome

A

matrilineal (mitochondrial) 20%

de novo mutation

X linked recessive

autosomal recessive

so many patterns because so many genes are involved

present in mtDNA, nuclear DNA, X chromosomes

72
Q

where are most mito. proteins encoded

A

on nuclear genome

synthesised in cytoplasm and transported to mitochondria

most inherited disorders of mito. are related to changes in nuclear DNA rather than mtDNA

these mutations are inherited according to the classic Mendelian rules, not mitochondrial (matrilineal) inheritance

73
Q
A
74
Q

mutations where cause the majority of PDH complex deficiencies

A

in the X linked pyruvate dehydrogenase (E1) and α subunit (PDHA1) [nuclear DNA]

inheritance pedigree may appear autosoma lrecessive because parents are not usually affected

in females (XX), a mutation would have to occur in both copies ofthe gene to cause the disorder

unlikely, so males are affected by X linked recessive disorders much more frequently than females

75
Q

how to prevent passing on your hereditary mitochondrial disease

A

mito. transplantation/donation

can be done before or after fertilisation

3 parent embryo

76
Q

things to remember

A

GGE (33 decks)

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