7 - Mitochondrial Disease Flashcards
Mitochondrial DNA
Found in cell mitochondria and contains genetic material only from the mother
Nuclear DNA
Found in cell nucleus and contains genetic material from both parents
Examples of diseases that result from mitochondrial dysfunction
- Mitochondrial diseases (most common genetically inherited metabolic diseases)
- Neuromuscular diseases
- Dementia and neurological disorders
- Diabetes and obesity
- Cancer
mtDNA mutations
- 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
What does diagnosis of mtDNA mutations rely on
- Sequencing
- Biopsies
- Enzymatic tests
Homoplasmic inheritance
- All copies of the mitochondrial genome are identical
- 100% chance all offspring will inherit the disease
Heteroplasmic inheritance
Coexistence of mutant and wildtype mtDNA within the same cell
Example of diseases caused by mutations in protein encoding genes
Maternally inherited Leigh syndrome
Example of diseases caused by mutations in tRNA
Mitochondrial encephalopathy
Examples of diseases caused by mutations in rRNA genes
Aminoglycoside-induced non-syndromic deafness
Examples of diseases caused by mutations in rearrangements
Diabetes and deafness
How do mutations in mitochondrial genes cause disease
- Destabilise the secondary or tertiary structure of
RNAs - Impair the processing of RNAs
- Impair the recognition by tRNA synthetases
- Impair protein synthesis
How can mutant mitochondria be eliminated
Nucleus removed from mothers egg and inserted into another females’ egg with healthy mitochondria
Gene therapies for mitochonrial diseases
- Using protein based therapeutic designed to target only the mutant mtDNA or mtRNA.
- Import into mitochondria using existing protein
import pathways
Why are CRISPR technologies not possible in
mammalian mitochondria
As they don’t import RNA
WHy is diagnosis of mitochondrial diseases caused by nuclear DNA mutations challenging
Because the diseases are multisystemic and involve multiple different specialists
Mitochondrial disease
- 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
Diagnosis of mitochondrial disease
- 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
RNase P 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
