7 - Mitochondrial Disease

Question 1

Mitochondrial DNA

Answer 1

Found in cell mitochondria and contains genetic material only from the mother

Question 2

Nuclear DNA

Answer 2

Found in cell nucleus and contains genetic material from both parents

Question 3

Examples of diseases that result from mitochondrial dysfunction

Answer 3

• Mitochondrial diseases (most common genetically inherited metabolic diseases)
• Neuromuscular diseases
• Dementia and neurological disorders
• Diabetes and obesity
• Cancer

Question 4

mtDNA mutations

Answer 4

• Maternal inheritance (affected father yield no affected children)
• Random distribution of amount of mtDNA to offspring
• Severity of symptoms linked to load of mutant mtDNA

Question 5

What does diagnosis of mtDNA mutations rely on

Answer 5

• Sequencing
• Biopsies
• Enzymatic tests

Question 6

Homoplasmic inheritance

Answer 6

• All copies of the mitochondrial genome are identical
• 100% chance all offspring will inherit the disease

Question 7

Heteroplasmic inheritance

Answer 7

Coexistence of mutant and wildtype mtDNA within the same cell

Question 8

Example of diseases caused by mutations in protein encoding genes

Answer 8

Maternally inherited Leigh syndrome

Question 9

Example of diseases caused by mutations in tRNA

Answer 9

Mitochondrial encephalopathy

Question 10

Examples of diseases caused by mutations in rRNA genes

Answer 10

Aminoglycoside-induced non-syndromic deafness

Question 11

Examples of diseases caused by mutations in rearrangements

Answer 11

Diabetes and deafness

Question 12

How do mutations in mitochondrial genes cause disease

Answer 12

• Destabilise the secondary or tertiary structure of
  RNAs
• Impair the processing of RNAs
• Impair the recognition by tRNA synthetases
• Impair protein synthesis

Question 13

How can mutant mitochondria be eliminated

Answer 13

Nucleus removed from mothers egg and inserted into another females’ egg with healthy mitochondria

Question 14

Gene therapies for mitochonrial diseases

Answer 14

• Using protein based therapeutic designed to target only the mutant mtDNA or mtRNA.
• Import into mitochondria using existing protein
  import pathways

Question 15

Why are CRISPR technologies not possible in
mammalian mitochondria

Answer 15

As they don’t import RNA

Question 16

WHy is diagnosis of mitochondrial diseases caused by nuclear DNA mutations challenging

Answer 16

Because the diseases are multisystemic and involve multiple different specialists

Question 17

Mitochondrial disease

Answer 17

• Some affect many organs and some few
• Some are more severe than others
• Some occur early in life and some later
• Same mutation can result in diverse phenotypes
• Different mutations can have a same phenotype

Question 18

Diagnosis of mitochondrial disease

Answer 18

• Long range PCR of mtDNA
• Ion Torrent sequencing of mtDNA
• Exome or whole genome sequencing
• Variant cells and linkage analyses
• Genotyping of family members
• Functional validation of the mutation

Question 19

RNase P subunits

Answer 19

• MRPP1, MRPP2 and MRPP3
• All three proteins are required for cleavage
• No requirement for a catalytic RNA
• Mutations in all three proteins cause disease