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genetic basis of disease > Mitochondrial biology and genetics in diagnostic practice > Flashcards

Mitochondrial biology and genetics in diagnostic practice Flashcards

1
Q

What is mitochondrial genetics?

  • H…………../Variation of the DNA that en………… mitochondria (especially ………………. DNA, mtDNA, but also …………. DNA, nDNA

Diagnostic service and g…………. counselling for individuals or families with, or at risk of, mitochondrial disease

A

What is mitochondrial genetics?

  • Herability/Variation of the DNA that encode mitochondria (especially mitochondrial DNA, mtDNA, but also nuclear DNA, nDNA

Diagnostic service and genetic counselling for individuals or families with, or at risk of, mitochondrial disease

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2
Q

All the parts with in eukaryotic cell

  • mic…………………
  • ve……..
  • cy…………
  • rough en……………….. reticulum
  • ribo…………..
  • s…………. endoplasmic reticulum
  • …………. membrane
  • flag……………
  • lys………..
  • ## Go…. co……………..Parts of nucleus
  • chro………
  • nuclear en……………
    nuclear p………
  • nucl………….
A

All the parts with in eukaryotic cell

  • microtubules
  • vesicle
  • cytosol
  • rough endoplasmic reticulum
  • ribosomes
  • smooth endoplasmic reticulum
  • plasms membrane
  • flagellum
  • lysosome
  • ## Golgi complexParts of nucleus
  • chromatin
  • nuclear envelope
    nuclear pore
  • nucleolus
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3
Q

Basic structure of mitochondria

  • I…………… membrane
  • o………….. membrane
  • C…………..
  • Ma……………
A

Basic structure of mitochondria

  • Inner membrane
  • outer membrane
  • Cristae
  • Matrix
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4
Q

Basic structure of mitochondria

  • I……………. membrane
  • o……….. membrane
  • Cris……………
  • Ma………
A

Basic structure of mitochondria

  • Inner membrane
  • outer membrane
  • Cristae
  • Matrix
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5
Q

Mitochondria

  • fi………….
  • f…………..
  • mo……………
  • B……………..
  • Mi……………..
A

Mitochondria

  • fission
  • fusion
  • movement
  • Biogenesis
  • Mitophagy
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6
Q

glycolysis

gl. ………..
- ………..

glucose 6 …………………….

………………….. 6 phosphate

  • ATP

glyceraldehyde 3- ………………

2p + (2nad+>2NADH)

1,3 bi-phosph……………..

+2ATP

3-phosp…………….

3-phophoe…………….

+2ATP

pyruvate

A

glycolysis

glucose

  • ATP

glucose 6 phosphate

fructose 6 phosphate

  • ATP

glyceraldehyde 3- phosphate

2p + (2nad+>2NADH)

1,3 bi-phosphoglycerate

+2ATP

3-phosphoglycerate

3-phophoenolpyruvate

+2ATP

pyruvate

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7
Q

Processes linked to proton motive force

  • Pr………… import
  • ………. generation
  • ………./…….. exchange
  • ………….. generation
  • …………. transport
  • mito………… membrane pote………
  • … transport

Processes linked to electron flow

  • reactive ox………..species sign………
  • nucle………. pools
  • on………… c………metabolism
  • NA……… generation
A

Processes linked to proton motive force

  • Protein import
  • ATP generation
  • ATP/AFP exchange
  • NADPH generation
  • calcium transport
  • mitochondrial membrane potential
  • Pi transport

Processes linked to electron flow

  • reactive oxygen species signalling
  • nucleotide pools
  • one carbon metabolism
  • NADPH generation
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8
Q

How does mtDNA differ from nuclear DNA

mtDNA vs nDNA

  • have a different ……………. code
  • have d…………… chr…………arrangements and g…….. copy n………….
    Have different i………….. patterns
  • Phe…………. expression

MtDNA genetics (like epigenetics) explains why nuclear DNA …………. ≠ phenotype

A

How does mtDNA differ from nuclear DNA

mtDNA vs nDNA

  • have a different genetic code
  • have different chromosomal arrangements and gene copy numbers
    Have different inheritance patterns
  • Phenotypic expression

MtDNA genetics (like epigenetics) explains why nuclear DNA genotype ≠ phenotype

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9
Q

Different chromosome and gene copy numbers

nDNA
-…. chromosomes
…… pairs of autos……….. (non-sex)
……. pair of sex chromosomes (f is XX, M is XY)

2 Copies/ alleles of every gene one from Mum and one from Dad

mtDNA

  • Multiple mitochondrial n………………..
  • Multiple mtDNA copies, usually from mum
  • Number is ………. type specific
A

Different chromosome and gene copy numbers

nDNA
-4 chromosomes
22 pairs of autosomes (non-sex)
1 pair of sex chromosomes (f is XX, M is XY)

2 Copies/ alleles of every gene one from Mum and one from Dad

mtDNA

  • Multiple mitochondrial nucleoids
  • Multiple mtDNA copies, usually from mum
  • Number is cell type specific
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10
Q

Different inheritance patterns

nDNA
- ……………

mtDNA
- ………………

A

Different inheritance patterns

nDNA
- Mendelian

mtDNA
- Maternal

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11
Q

Mendelian genetic traits (nDNA)

  • A………………… inheritance - encoded for by aut………………..
  • …..-linked inheritance, e.g. haemophilia
  • Rec………… disorder - both relevant alleles are non-functional for phe………, e.g. c…….. …………
  • Dominant disorder - only 1 allele needs to be mut……… for phenotype, e.g. Huntington’s
  • Homozy………./ Hetero………
A

Mendelian genetic traits (nDNA)

  • Autosomal inheritance - encoded for by autosomes
  • X-linked inheritance, e.g. haemophilia
  • Recessive disorder - both relevant alleles are non-functional for phenotype, e.g. cystic fibrosis
  • Dominant disorder - only 1 allele needs to be mutated for phenotype, e.g. Huntington’s
  • Homozygosity/ Heterozygosity
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12
Q

Maternal Genetic Traits (mtDNA)

  • Maternal inheritance - encoded for by ………….

Mutant mtDNA > 60% for ……………..

Heteroplasm/ Homoplasmy

  • Mixture of DNA variants within a cell = ………….
  • One type of mtDNA within a cell -= ……………..
A

Maternal Genetic Traits (mtDNA)

Maternal inheritance - encoded for by mtDNA

Mutant mtDNA >60% for phenotype

Heteroplasm/ Homoplasmy

  • Mixture of DNA variants within a cell = heteroplasmy
  • One type of mtDNA within a cell -= homoplasmy
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13
Q

Why maternal :
sperm DNA is di…………
sperm DNA is eli……………

A

Why maternal? Because sperm mtDNA is:

  • Diluted
  • Eliminated
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14
Q

Abnormal mtDNA Inheritance
(Non-uniparental)

Examples

  • Paternal …………. tran…………..
  • Donor cell mtDNA transmission following nuclear genome transfer techniques like so……… ce…….. nu……….. and 3 Pa………. ……..
A

Abnormal mtDNA Inheritance
(Non-uniparental)

Examples

  • Paternal mtDNA transmission
  • Donor cell mtDNA transmission following nuclear genome transfer techniques like somatic cell nuclear and 3 Parent IVF
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15
Q

Mechanisms

  • Certain mtDNA sequences have a re………… advantage
  • M……….. in nuclear genes that are involved in the elimination of “foreign” mi………… (lysosome/ autophagy pathways)

Combination of the two

A

Mechanism(s)?

Certain mtDNA sequences have a replicative advantage

Mutation in nuclear genes that are involved in the elimination of ‘foreign’ mitochondria (lysosome/ autophagy pathways)

Combination of the two

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16
Q

Maintenance of mtDNA/OXPHOS/mitochondria is highly dependent on nu………..-mito………….interactions

If they are disrupted e.g. through mutation of ………….. genes or ……….. genes encoding mtDNA transcription/replication factors or numerous other mitochondrial proteins you can get dysfunctional mitochondria and disease

A

Maintenance of mtDNA/OXPHOS/mitochondria is highly dependent on nuclear-mitochondrial interactions

If they are disrupted e.g. through mutation of mtDNA genes or nDNA genes encoding mtDNA transcription/replication factors or numerous other mitochondrial proteins you can get dysfunctional mitochondria and disease

17
Q

Mutation in nDNA and mtDNA genes that affect the integrity of OXPHOS are associated with numerous diseases

  • …….. disorders (inborn errors of metabolism)
  • Neuro………………..
  • Ag………..
  • Me……………..
  • C…………
A

Mutation in nDNA and mtDNA genes that affect the integrity of OXPHOS are associated with numerous diseases

  • MRC disorders (inborn errors of metabolism
  • Neurodegeneration
  • Ageing
  • Metabolic
  • Cancer
18
Q

MtDNA Genotype ≠ Phenotype

  • M………..
  • M……….. load (%heteroplasmy)
  • A…….
  • Envi………….
    .
    …….. mutant load is often required for a phenotypic affect to be observed
A

MtDNA Genotype ≠ Phenotype

Mutation

Mutant load (%heteroplasmy)

Tissue

Age environment

*> 60% mutant load is often required for a phenotypic affect to be observed

19
Q

Why so many mutants in mtDNA

  • little protection by h………. (although mtDNA - specific transcription factor …, TF….., is thought to play a histone - like role)
  • Proximity to da. ……… rea…….. oxygen species produced by the OXPHOS system
  • Lower proof reading ability of the mtDNA specific DNA polymerase (POLG)
A

Why so many mutants in mtDNA

  • little protection by histones (although mtDNA - specific transcription factor A, TFAM, is thought to play a histone - like role)
  • Proximity to damaging reactive oxygen species produced by the OXPHOS system
  • Lower proof r……….. ability of the mtDNA specific DNA polym…….. (POLG)
20
Q

Mitochondrial disease

  • For the purposes of this seminar mitochondrial disease will represent only disorders of the mitochondrial respiratory chain (MRC) or mitoc……… elec……. transport chain
  • In addition, defects in ATP synthase (complex …..) will also be included as a disorder of the MRX

Can be caused by m………… in nuclear DNA or mtDNA

A

Mitochondrial disease

  • For the purposes of this seminar mitochondrial disease will represent only disorders of the mitochondrial respiratory chain (MRC) or mitochondrial electron transport chain
  • In addition, defects in ATP synthase (complex V) will also be included as a disorder of the MRX

Can be caused by mutations in nuclear DNA or mtDNA

21
Q

MRC disorders represent the most common group of inborn errors of metabolism

  • Incidence of 1 in 50……
  • MRC disorders are generally pro……… and multi-sys………
  • Typically affected organs are those with high energy demands: Neur………. and neu………… presentations the commonest
A

MRC disorders represent the most common group of inborn errors of metabolism

  • Incidence of 1 in 5000
  • MRC disorders are generally progressive and multi-systemic
  • Typically affected organs are those with high energy demands: Neuromuscular and neurological presentations the commonest
22
Q

Complexity of genetics can lead to diverse clinical features:

           - Any  Sy........
		- Any Org.... or T...........
		    - Any Age of Prese............
		       - Any mode of in..........
A

Complexity of genetics can lead to diverse clinical features:

           - Any  Symptom
		- Any Organ or Tissue
		    - Any Age of Presentation
		       - Any mode of inheritance
23
Q

Cli……….. Picture > B…………… > H…………. .> Mo……………. Bi…………, including genetics

A

Clinical Picture > Biochemistry > Histochemistry > Molecular Biology, including genetics

24
Q

Diagnostic algorithm

Clinical presentation indicative of mitochondrial disease > …………. sample for biochemistry/genetic studies > …………… result/mutation or ….. evidence of an abnormality/mutation > Muscle ……….. for biochemistry, histology + further genetic studies

A

Diagnostic algorithm

Clinical presentation indicative of mitochondrial disease > Blood sample for biochemistry/genetic studies > Abnormal result/mutation or no evidence of an abnormality/mutation > Muscle biopsy for biochemistry, histology + further genetic studies

25
Q

Biochemical Diagnosis

  • No real …………… of the disease so it can’t be diagnosed by N… …….. …………………
    = There a few initial tests that can be undertaken in a ……… sample (low-invasive)
A

Biochemical Diagnosis

No real Biomarkers of the disease so it can`t be diagnosed by New Born Screening
There a few initial tests that can be undertaken in a blood samples (low-invasive)

26
Q

Biochemical Diagnosis

  • Mutations in mtDNA + some nuclear DNA mutations can also be assessed in blood

Blood can also be used to measure some non specific markers of MRC dysfunction

  • Increased a…………. in blood and CSF
  • Increased py………….. in blood and CSF
  • Increased La…………… in blood and CSF
A

Biochemical Diagnosis

  • Mutations in mtDNA + some nuclear DNA mutations can also be assessed in blood

Blood can also be used to measure some non specific markers of MRC dysfunction

  • Increased alanine in blood and CSF
  • Increased pyruvate in blood and CSF
  • Increased Lactate in blood and CSF
27
Q

Serum lactate
- The determination of plasma or whole blood lactate levels is commonly used to assess evidence of ……. impairment

  • Patient la…………. levels are compared to a reference range
  • The reference range for human serum lactate concentrations is 0.5-2.1mM
A

Serum lactate
- The determination of plasma or whole blood lactate levels is commonly used to assess evidence of MRC impairment
]
- Patient lactate levels are compared to a reference range

  • The reference range for human serum lactate concentrations is 0.5-2.1mM
28
Q

Biochemical Diagnosis

MRC impairment may impair the Krebs cycle

Accumulation of………. cycle intermediates in the ………. (urine organic acid analysis)

Accumulation of krebs cycle intermediates is ,,,,,,,,,,,,, indicator of ……….. dysfunction

A

Biochemical Diagnosis

MRC impairment may impair the Krebs cycle

Accumulation of krebs cycle intermediates in the urine (urine organic acid analysis)

Accumulation of krebs cycle intermediates is indirect indicator of MRC dysfunction

29
Q

Biochemical Diagnosis

  • At present there is no specific marker of MRC dysfunction - elevated blood lactate levels or accumulation of Krebs cycle intermediates are indicators only

May show no abnormality in patients with MRC Disease

The “gold standard for biochemically diagnosing evidence of MRC evidence of MRC dysfunction is to assess MRC enzyme activities in skeletal muscle biopsy

A

Biochemical Diagnosis

  • At present there is no specific marker of MRC dysfunction - elevated blood lactate levels or accumulation of Krebs cycle intermediates are indicators only

May show no abnormality in patients with MRC Disease

The “gold standard for biochemically diagnosing evidence of MRC evidence of MRC dysfunction is to assess MRC enzyme activities in skeletal muscle biopsy

30
Q

Sample Handling of muscle biopsy

  • Skeletal muscle (5….-1………mg)
  • Fla…….. fro……. as bedside
  • Sto……. at -70*c
  • trans…………. in dry ice
  • sto……. at -70*c
  • homo……….. (1:9w/v)
  • Fre…… Th……. (x3)
  • Assay
A

Sample Handling of muscle biopsy

  • Skeletal muscle (50-100mg)
  • Flash frozen as bedside
  • Store at -70*c
  • transported in dry ice
  • store at -70*c
  • homogenise (1:9w/v)
  • Freeze Thaw (x3)
  • Assay
31
Q

CoQ10 assessement by HPLC analysis

Function: Electron carrier in the MRC + important lip…….. solu………… antioxidant

Analysis: Determined in skeletal muscle by …….. analysis using ……. detection at 2………nm

A

CoQ10 assessement by HPLC analysis

Function: Electron carrier in the MRC + imporant lipid soluble antioxidant

Analysis: Determined in skeletal muscle by HPLC analysis using UV detection at 275nm

32
Q

MRC Complex ranges

Complex I 0.1…..-0.2…….
Complex II/III 0.0……- 0.2………
Complex IV 0.01………-0.03……

A

MRC Complex ranges

Complex I 0.140-0.298
Complex II/III 0.040- 0.204
Complex IV 0.014-0.034

genetic basis of disease (3 decks)

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