Mitochondrial genetics

Question 1

What are the two types of nontraditional patterns of inheritance we’ve discussed?

Answer 1

Mitochondrial inheritance and uniparental disomy

Question 2

Mutations affecting mitochondria alter what mitochondrial function?

Answer 2

ATP production

Question 3

Mitochondrial porins allow tansit of molecules of what size?

Answer 3

<5000 Da

Question 4

True or false: many of the proteins that function in the mitochondria are encoded for by mitochondrial DNA, are made in the matrix of the mitochondria, and are transported to the cytoplasm.

Answer 4

False: many of the proteins that function in the mitochondria are encoded for by nuclear DNA, are made in the cytoplasm, and transported to the mitochondria.

Question 5

What portion of the circular mtDNA is coding region?

Answer 5

80%

Question 6

True or false: mtDNA uses different codons than nuclear DNA.

Answer 6

True

AGA and AGG are also stop codons

Question 7

Why are the mitochondria in sperm not transmitted to the fertilized egg?

Answer 7

The mitochondria in sperm are ubiquinated for destruction.

Question 8

Although mitochondrial traits will be transmitted from a mother to all her children, why may some of the traits not be expressed phenotypically?

Answer 8

Incomplete penetrance and variable expressivity.

Question 9

What is replicative segregation?

Answer 9

Multiple copies of mtDNA within each mitochondrion replicate and assort randomly. mtDNA segregates randomly to mitochondria as they divide, and the mitochondria are distributed randomly between the two daughter cells.

Question 10

How do mitochondria divide?

Answer 10

Simple fission.

Question 11

What is homoplasmy?

Answer 11

A pure population of mitochondria, either all wild type or all mutant.

Question 12

What is heteroplasmy?

Answer 12

A mixture of mutant and wilt type mitochondria or their DNA within them.

Question 13

Are most mitochondrial disorders produced by homoplasmy or heteroplasmy? What determines the severity of the disorder.

Answer 13

Heteroplasmy; severity depends on fraction of mutant mitochondria present in relevant tissues (must pass disease threshold)

Question 14

Which one of these do mt disorders NOT show:
Variable expressivity
Incomplete penetrance
variable age of onset
Pleiotropy

Answer 14

Mt disorders show them all actually.

Question 15

Describe the mitochondrial genetic bottleneck?

Answer 15

During oogenesis (in oocyte precursors), the number of mitochondria present is dramatically reduced (~100/cell) prior to expansion (~100k copies of mtDNA in mature oocyte), which produces variability of mitochondrial content in offspring.

Question 16

Which is more prone to mutation, mtDNA or nuclear DNA and why?

Answer 16

mtDNA ~10X more prone to mutation than nuclear DNA. Due to ROS from OxPhos, lack of proofreading, and limited DNA repair mechanisms.

Question 17

True or false: female heteroplastic for deletion mutations in mtDNA generally transmit the mutant mitochondria to her offspring.

Answer 17

False: the mechanism is unknown, but there is selection to NOT transmit mutant mitochondria to offspring.

Question 18

How many copies of mtDNA are in each mitochondria and how many mitochondria are in each cell?

Answer 18

2-10 copies of mtDNA per mitochondrion, and hundreds of mitochondria per cell (thousands in oocyte)

Question 19

What is the phenotypic threshold for heteroplasmic mitochondrial disorders?

Answer 19

60% for deletions and 90% for other mutations.

Question 20

What does LHON stand for?

Answer 20

Leber hereditary optic neuropathy.

Question 21

What mutation resutls in LHON?

Answer 21

Results from mutation in NADH dehydrogenase subunit 1 or 4 genes.
95% have one of three mutations, 2 of which are in subunit 1 (most and least sever), and the other in subunit 4 (intermediate).
Environmental (smoking and alcohol) and other genetic factors (being male) have an effect on the severity.

Question 22

Are LHON mutations mostly hetero- or homo-plasmic?

Answer 22

homoplasmic

Question 23

Why do LHON and MERRF worsen with age?

Answer 23

Mitochondrial function declines with age due to accumulated mutations.

Question 24

Which of the following is not a symptom of LHON?
Initial painful vision loss
Blurred central vision
onset in twenties (can be later)
progression to blindness is rapid, affecting both eyes equally
may develop cardiomyopathy

Answer 24

Initial vision loss is painless.

Question 25

Why do >50% of sons and 85% of daughters of mothers with LHON NOT develop symptoms?

Answer 25

Incomplete penetrance.

Question 26

What does MERRF stand for?

Answer 26

Myoclonic epilepsy with ragged-red fibers

Question 27

What mutation leads to MERRF?

Answer 27

Mutation in tRNA^Lys gene. 90% have one of three mutations which reduce the amount of charged tRNA^Lys by half, which reduces the efficiency of protein translation.

Question 28

Are most MERRF mutations hetero- or homo-plasmic?

Answer 28

Heteroplasmic

Question 29

Which of the following is not a symptom of MERRF?
Myoclonic epilepsy
mitochondrial myopathy with ragged red fibers (clumped mitochondria)
Onset in childhood or adult life
Slowly progressive or rapid deterioration
Sensoneureal hearing loss
ataxia
renal dysfunction
diabetes
cardiomyopathy
dimentia

Answer 29

All are symptoms of MERRF

Question 30

Why is blood testing not an effective method of testing at-risk family members for MERRF?

Answer 30

Replicative segregation and tissue selection means mutation may not be detectable in blood (i.e. what you see in blood may not be what you see in other tissues). Even positive results do not predict the severity of the disorder.