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1PATH3305 Medical Genetics > Lecture 7: Mitochondrial genetic in Health L2 > Flashcards

Lecture 7: Mitochondrial genetic in Health L2 Flashcards

1
Q

Mitochondria are composed of proteins encoded by two genomes: 2

A
  1. Nuclear DNA
  2. Mitochondrial DNA
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2
Q

Mitochondrial DNA features:

A
  1. (mDNA) is found in cell mitochondria
  2. contains genetic material ONLY FROM THE MOTHER
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3
Q

Nuclear DNA features

A
  1. (nuDNA) is found in the CELL NUCLEUS
  2. Contains genetic material from BOTH PARENTS
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4
Q

Which genome causes mitochondrial diseases..

A
  1. Mutations in mtDNA or nuclear DNA genes that make up mitochondria can cause mitochondrial disease
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5
Q

Mitochondrial dysfunction leads to diverse pathologies and diseases….7

A

1 * Neuromuscular diseases

2 * Dementia and neurological disorders

3 * Diabetes and obesity

4 * Liver disease

5 * Heart disease

6 * Cancer

7 * Ageing

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6
Q

most common genetically inherited metabolic diseases:

A

Mitochondrial diseases

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7
Q

ORGAN AND MITOCHONDRIAL DNA causes disease = 11

A
  1. EYE:
    - optic neuropathy
    - ophthalmoplegia
    - retinopathy
  2. LIVER:
    - Hepatopathy
  3. KIDNEY:
    - Fanconi’s syndrome
    - glomerulpathy
  4. PANCREAS
    - Diabetes mellitus
  5. BLOOD
    - Pearson’s syndrome
  6. INNER EAR
    - Sensorineural hearing loss
  7. COLON
    - Pseudo-obstruction
  8. BRAIN
    - seizures
    - myoclonus
    - ataxia
    - stoke
    - dementia
    - migraine
  9. SKELETAL MUSCLE
    - weakness
    - fatigue
    - myopathy
    - neuropathy
  10. HEART
    - Conduction disorder
    - wolf-parkinson-white syndrome
    - cardiomyopathy
  11. NUCLEAR DNA —-SUBUNITS —-OXIDATIVE PHOSPHORYLATION —-NUCLEAR DNA
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8
Q

Mitochondrial dysfunction leads to diverse pathologies and diseases - STATISTICS

A

1 in 8,000 at risk

1 in 15,000 to be affected

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9
Q

Mitochondria are composed of proteins encoded by two genomes

A

UNDERSTAND SLIDE 5 DIAGRAM AND PROCESS

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10
Q

Mitochondrial DNA mutations and heteroplasmy: 4

A
  1. MtDNA mutations have maternal inheritance

2 *Stochastic distribution of mtDNA

3 *Severity of symptoms often can be linked to the
load of mutant mtDNA

4 *Transfer of mutant mtDNA is not well
understood

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11
Q

*Diagnosis of mtDNA mutations in the clinic
relies on: 3

A
  1. Sequencing

2 * Biopsies

3 * Enzymatic tests

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12
Q

SLIDE 6 MITOCHONDRIAL INHERITANCE

A

STUDY FLOW CHART

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13
Q

SLIDE 7 MITOCHONDRIAL…OOCYTE MATURATION AND mtDNA amplification + fertilisation

A

STUDY FLOW CHART

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14
Q

SLIDE 8 Mitochondrial DNA mutations and heteroplasmy

A

STUDY FLOW CHART

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15
Q

Mutations in mitochondrial genes cause disease…

Protein-encoding genes = 3

A

1 * Neurogenic weakness, ataxia and retinitis pigmentosa (NARP) – T8993G/C

2 * Maternally inherited Leigh syndrome (MILS) – T8993G/C

3 * Leber’s hereditary optic neuropathy (LHON) – G3460A, G11778A, T14484C and A14495G

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16
Q

Mutations in mitochondrial genes cause disease

tRNA genes = 3

A

1 * Mitochondrial encephalopaty with lactic acidosis and stroke-like episodes (MELAS) – A3243G

2 * Myoclonic epilepsy with ragged red fibres (MERRF) – A8344G

3 * Non-syndromic sensorineural deafness – A7445G

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17
Q

Mutations in mitochondrial genes cause disease

rRNA genes = 1

A

Aminoglycoside-induced non-syndromic deafness – A1555G

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18
Q

Mutations in mitochondrial genes cause disease:

Rearrangements = 3

A

1 * Chronic progressive external ophthalmoplegia

2 * Kearns-Sayre syndrome

3 * Diabetes and deafness

19
Q

Mutations in mitochondrial genes cause mitochondrial diseases = 12

A
  1. Mutations in mitochondrial genes:
  2. Frequency 1:4000

3 *Destabilize the secondary or tertiary structure of RNAs
…4 * A3243G MELAS
…5 * A8344G MERRF

6 *Impair the processing of RNAs:
….7 * A3302G cardiomyopathy
…..8 * A5559G

9 *Impair the recognition by tRNA synthetases
…..10 * 5- taurinomethyl-2-thiouridine (τm5 s2 U)

11.*Impair protein synthesis
….12 * 5- taurinomethyl-2-thiouridine (τm5 s2 U)

20
Q

Mitochondrial Donation

  • Eliminating mutant mitochondria = 4
A

1 *Precludes from transmitting inherited mitochondrial disease to future generations

2 *Already in practice in the United Kingdom

3 *Requires in vitro fertilization

4 *The risks are minimal and research into any
potential risks is carried out

21
Q

Mitochondrial Donation
Eliminating mutant mitochondria…DIAGRAM

A

UNDERSTAND FLOW CHART IN SLIDE 11

22
Q

Gene therapies for
mitochondrial diseases

Modulating the mutant heteroplasmy load: 4

A

1 *Using protein based therapeutic designed to target only the mutant mtDNA or mtRNA.

2 *Import into mitochondria using existing protein import pathways

3 *CRISPR technologies not possible in mammalian mitochondria as they don’t import RNA

4 *Current gene therapies are under research and development

23
Q

Gene therapies for
mitochondrial diseases
Modulating the mutant heteroplasmy load…2 FLOW CHARTS ARE IMPORTANT

A

UNDERSTAND SLIDE 12 DIAGRAMS

24
Q

Inheritance of mitochondrial diseases caused by mutations in nuclear encoded proteins….

Nuclear mutations follow autosomal dominant or recessive inheritance:

A

1 *Diagnosis of mitochondrial diseases caused by nuclear DNA mutations in the clinic is
challenging because the diseases are multisystemic and involve multiple different specialists.

2 *There are no treatments or cures to date only
palliative care for patients is available.

25
Q

Diagnosis of nuclear DNA mutations relies on a
combination of: 3

A
  1. Sequencing
  2. Biopsies
  3. Enzymatic tests
26
Q

Inheritance of mitochondrial diseases caused by
mutations in nuclear encoded proteins = SLIDE 12

A

SLIDE 12

    1. Autosomal recessive
    1. Consanguineous autosomal recessive
    1. autosomal dominant
27
Q

INTEGRATED APPROACH FOR MITOCHONDRIAL DISEASE DIAGNOSIS …3

A
  1. METABOLIC TESTING:
    – Blood
    – urine
    - CSF
  2. Muscle testing
    - liver tissue respiromtry
    - muscle pathology
    - OXPHOSEnzymology
    - Protein chemistry
    - C0Q10
  3. GENETIC TESTING:
    - mt DNA
    - Nuclear DNA
28
Q

Nuclear mutations in genes encoding mitochondrial proteins…8

A
  1. Gene expression defects
    * Leigh syndrome – LRPPRC,
    TACO1
    * Alpers, CMT – POLg
    * PEO – Twinkle
  2. Assembly defects
    * Leigh syndrome – SURF1
    * Cardioencephalomyopathy – SCO2
    * Neonatal-onset hepatic failure
    and encephalopathy – SCO1
    * Leigh and De Toni-FanconiDebre syndrome – COX10
  3. Homeostasis and import
    * Friedreich’s ataxia –frataxin
    * Hereditary spastic paraplegia – paraplegin
    * Deafness-dystonia syndrome – DDP
    * Dominant optic atrophy – OPA1
  4. Complex I deficiency
    * Leigh and Leigh-like syndrome
    NDUFS4, NDUFS7 and NDUFS8
    * Hypertrophic cardiomyopathy and
    encephalomyopathy – NDUFS2
    * Macrocephaly, leucodystrophy and
    myoclonic epilepsy – NDUFV1
  5. Complex II deficiency
    * Leigh and Leigh-like syndrome
  6. Complex III deficiency
    * Encephalopathies, GRACILE
    syndrome – BCS1L, UQCRB and UQCRQ
  7. Complex IV deficiency
    * Leigh syndrome – COX15, COX8A
  8. Complex V deficiency
    * Cardiomyopathy – ATPAF2
29
Q

Nuclear mutations in genes encoding mitochondrial proteins…DIAGRAM ..understand the process

A

SLIDE 14

30
Q

Mitochondrial Diseases affect different organs and have varying severity = 6

A
  1. It is important to identify the genetic cause of mitochondrial diseases to
    understand how it leads to disease and identify potential treatments.

2 * Some diseases affect many organs and some few

3 * Some diseases are more severe than others

4 * Some diseases occur early in life and some later

5 * A same mutation can result in diverse phenotypes

6 * Different mutations can have a same phenotype

31
Q

Molecular and functional diagnosis of Mitochondrial Disease = IMPORTANT

A

KNOW FLOW CHART AND DIAGRAM …SLIDE 16 TO 19

32
Q

Isolated Complex IV deficiency in a patient with a cytochrome oxidase subunit 1 (CO1) mutation = 5

A
  1. Patient - a 10 year old girl

2 *Increased lactic acidosis

3 *Early onset retinitis pigmentosa

4 *Ataxia and peripheral neuropathy

5 *Mutation in CO1 gene coding for a scaffold
protein required for Complex IV activity

33
Q

Limitations of cell models for mitochondrial disease research = 3

A
34
Q

Limitations of cell models for mitochondrial disease research = 3

**Animal models of disease are the best in vivo tool for clinical research

A

Animal models of disease are the best in vivo tool for clinical research

1 * C. elegans (worms), Drosophila (fruit flies), Mus musculus (mice)

2 * Availability of material, genetic manipulation and physiological relevance

3 * Investigating the disease in the affected tissues

35
Q

Impaired protein synthesis can generate diverse phenotypes = 7

A
  1. Mrps34….Overall impaired translation…ORAGNS ..MITOCHONDRIAL DISEASE
  2. Taco1…Impaired COXI translation…ORGANS…Mitochondrial Disease
  3. Ptcd1 Het…Decreased translation… ORGANS …HYPERTROPHIC, CARDIOMYOPATHY, METABOLIC DISEASE
  4. Ptcd1, Elac2 and Mrpp3 KO…Loss of translation…DILATED CARDIOMYOPATHY
  5. Mrps12…error-prone translation..ORGANS…Liver Regeneration
  6. Mrps12….Hyper-accurate translation…ORGANS…DIALTED CARDIOMYOPATHY
  7. Translation factor…uncoordinated translation…ORGANS….Myopathy and cardiomyopathy
36
Q

Mitochondrial RNA processing is required for energy production… 4

A

1.RNase P cleaves the 5’ end of mitochondrial tRNAs and
is composed of 3 subunits: MRPP1, MRPP2 and MRPP3
*All three proteins are required for cleavage
*No requirement for a catalytic RNA
*Mutations in all three proteins cause disease

  1. *Loss of MRPP3 is embryonic lethal and heart and skeletal muscle KO causes cardiomyopathy and lethality by 11 weeks
  2. *5′ tRNA processing precedes 3′ tRNA processing

4 *RNA processing links transcription to translation via mitoribosome assembly and this essential for respiration

37
Q

RNase P cleaves the 5’ end of mitochondrial tRNAs and
is composed of 3 subunits: MRPP1, MRPP2 and MRPP3 = 3

A

1 *All three proteins are required for cleavage

2 *No requirement for a catalytic RNA

3 *Mutations in all three proteins cause disease

38
Q

Mitochondrial RNA processing is required
for energy production DIAGRAMS

A

IMPORTANT ..LOOK AT SLIDE 24

MRPP3 ..KNOW PROCESS AND DIAGRAM

39
Q

5′ tRNA processing in mitochondria

….RNA sequencing: 3

A

1 * RNA-Seq enabled capture of tRNAs contained within longer precursor transcripts

2 * PARE enabled capture of 5’ RNA ends

3 * Combined they identified impaired mitochondrial RNA processing

40
Q

Mutations in mitochondrial RNA processing enzymes cause disease….

…Identified a mutation in MRPP1: 4

A
  1. Early onset mitochondrial disease
    • Combined OXPHOS defect, multi-systemic disorder, both children died at ~5 months

3 * Decreased stability of the MRPP1 protein

4 * Impaired mitochondrial RNA processing

41
Q

LRPPRC is a general RNA chaperone required for mRNA stability…

….The leucine-rich pentatricopeptide repeat
cassette (LRPPRC) protein:

A

1 * A A354V mutation in LRPPRC causes the autosomal recessive French-Canadian variant
Leigh Syndrome

2 * Loss of LRPPRC is embryonic lethal and heart
and skeletal muscle-specific loss of LRPPRC causes dilated cardiomyopathy by 12 weeks
of age in mice

3 * LRPPRC is in a stable complex with SLIRP
that protects it from degradation

4 * The LRPPRC/SLIRP complex is localized in
the mitochondrial matrix where it coordinates
mRNA translation by relaxing their secondary structure

42
Q

LRPPRC is a general RNA chaperone required for mRNA stability… DIAGRAM

A

UNDERSTAND AND DRAW

SLIDE 27

43
Q

Summary: 4

A
  1. Mitochondrial diseases are the most common genetically inherited metabolic disorders.
    - They can affect young infants as well as adults and the severity of the diseases varies and most often is lethal.

2 * Mitochondrial diseases have several different inheritance modes.

3 * There are no cures for mitochondrial disease so there is an urgent need to find therapeutics and treatments.
- Diagnosis for mitochondrial diseases has improved with
the advances of next generation technologies, however there are still gaps in functional validation of putative pathogenic genes.

4 * There are many different models that can be used to understand the pathology of
mitochondrial diseases and reveal therapeutic targets for drug development

1PATH3305 Medical Genetics (20 decks)

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