Genetics of Mitochondrial Disorders Flashcards
What are the three classifications of mitochondrial diseases?
1) . Primary mtDNA disorders.
2) . mtDNA maintenance disorders (secondary mtDNA disorders).
3) . Nuclear gene disorders with no effect on mtDNA.
What are the 2 main subtypes of primary mtDNA disorders?
There are 2 main subtypes of primary mtDNA disorders.
1) . Point mutations:
- mainly occur in tRNA genes or protein coding genes.
- often heteroplasmic.
- maternally inherited.
2) . mtDNA rearrangements.
- typically large (approximately 2-8 kb deletions).
- heteroplasmic.
- usually sporadic.
What is the most common mtDNA point mutation?
- m.3243 is generally considered to be the most common pathogenic mtDNA, closely followed by common LHON mutations.
- Prevalence of m.3243A>G in newborns is 1 in 700.
- Associated disease incidence is much lower as individuals with low levels of mutation may be asymptomatic.
- Occurs in MT-TL1 gene, which encodes tRNALeu(UUA/UUG).
- Heteroplasmy levels highly variable between tissues.
What are the 3 most common mutations seen in LHON?
- m.11778G>A
- m.3460G>A
- m.14484T>C
- Together these 3 mutations account for >90% of LHON.
- Usually homoplasmic but heteroplasmic in some families.
- Lead to missense mutations in complex I subunits MT-ND4, MT-ND1 and MT-ND6 respectively.
What point mutation is associated with MERRF?
- Myoclonic epilepsy with ragged red fibres.
- m.8344A>G.
- Heteroplasmic, relatively uniform distribution between tissues.
- MT-TK encoding tRNA.
What is the most common mutation associated with Leigh syndrome and NARP?
- m.8993T>C/G.
- Primarily associated with maternally inherited Leigh syndrome and NARP (neurogenic muscle weakness, ataxia, and retinitis pigmentosa).
- Heteroplasmic (often very high levels), relatively uniform distribution between tissues.
- Missense mutation in complex V (ATP synthase) subunit MT-ATP6.
What is the 2nd category of primary mitochondrial DNA disorders?
2) . mtDNA rearrangements:
- Typically large (approximately 2-8 kb deletions).
- Heteroplasmic - Levels of heteroplasmy highly variable between tissues. Rarely detectable in blood DNA from adults.
- Usually sporadic - Rare maternal inheritance may be associated with the presence of duplications - e.g. rare families with diabetes and deafness and rare reports of familial CPEO/KSS/Pearson.
- Clinical syndromes include:
1) . Pearson Syndrome - infantile sideroblastic anaemia.
2) . Kearns-Sayre syndrome - childhood-onset PEO, pigmentary retinopathy, and other features.
3) . Chronic progressive external opthalmoplegic (CPEO) - adult-onset relatively mild disorder.
Give an overview of secondary mtDNA disorders.
- mtDNA maintenance disorders (secondary mtDNA disorders).
- Two main types:
1) . Autosomal recessive mtDNA depletions syndrom.
2) . Autosomal dominant or recessive PEO. - Unique group of disorders involving defects in both of the genomes within cells. Primary nuclear gene defect in a gene that affects DNA replication / maintenance. Secondary mitochondrial DNA defect - tissue specific.
- May get mitochondrial depletion with too few copies of mtDNA or multiple deletions where many of the mtDNA copies that are present have deletions present.
- mtDNA depletions or multiple deletions lead to tissue-specific oxidative phosphorylation defects which in turn lead to disease symptoms.
- The POLG gene encodes the catalytic subunit of the polymerase gamma ATP polymerase. The accessory subunit is encoded by the POLG2 gene. Mutations in either of these two genes can lead to mitochondrial DNA disorders.
- Similarly, the mtDNA helicase which unwinds the mtDNA during replication is encoded by the PEO1 gene and the protein is often known as Twinkle - mutations in this gene can also lead to mtDNA maintenance disorders.
- Another example is the RRM2B gene which functions out in the cytosol and encodes a subunit of the p53RNR tetramer which converts NDPs into dNTPs. These dNTPs can then enter the mitochondria and contribute to replication of mtDNA. A number of other enzymes including DGUOK and TK2 have similar roles but these lie within the mitochondrion. Essentially, if any of the enzymes that are involved in regulating the availability of dNTPs are disrupted then this can lead to a mitochondrial DNA maintenance disorder (as in the example of RRM2B, DGUOK and TK2).
- There are additional genes where the function is not clearly known / we don’t understand how this has an impact on mtDNA maintenance - e.g. MPV17 which is located in the mitochondrial inner membrane and OPA1 and MFN2 that are known to be important in mitochondrial membrane fusion but exactly how this impacts on mitochondrial DNA maintenance is unclear.
Outline the different forms of mtDNA depletion syndromes.
1) . Hepatocerebral form:
- POLG (Alpers syndrome).
- DGUOK.
- MPV17.
- PEO1.
2) . Encephalomyopathic form:
- SUCLA2.
- SUCLG1.
- RRM2B.
- FBXL4.
3) . Myopathic form.
- TK2.
- MGME1.
4) . MINGIE (mitochondrial neurpgastrointestinal encephalopathy).
- TYMP.
- POLG.
- RRM2B.
5) . Cardiomyopathic form.
- AGK (Sengers syndrome - controversy over whether this is a mtDNA depletion sydrome)
ALL AUTOSOMAL RECESSIVE.
Outline the different forms of Progressive External Opthalmoplegia (PEO) with mtDNA deletions.
1) . Autosomal Dominant:
- POLG.
- SLC25A4.
- C10orf2 (Twinkly, PEO1).
- POLG2.
- RRM2B.
- DNA2.
- OPA1 - Optic Atrophy ‘plus’ syndrome.
2) . Autosomal Recessive:
- POLG.
- RRM2B.
- DGUOK.
- MPV17.
- TK2.
- MGME1.
Usually adult-onset in contrast to the mtDNA depletions which are usually infantile or childhood onset disorders.
Summarise some examples of nuclear gene disorders with no effect on the mtDNA.
Nuclear gene disorders with no effect on mtDNA:
- Autosomal disorders affecting subunits of the respiratory chain or assembly factors, such as recessive Leigh syndrome due to SURF1.
- Autosomal disorders of impaired mitochondrial protein translation, such as recessive pontocerebellar hypoplasia due to RARS2.
- Autosomal disorders of impaired mitochondrial dynamics such as dominant optic atrophy due to OPA1.
