Lecture 33 Flashcards
Describe heteroplasmy as it relates to mitochondrial genetic disease
heteroplasmy describes the mixture of normal and mutated mitochondria that can occur in a person with mitochondrial genetic disease or someone who is prone to it
normal and mutated mitochondria are randomly separated during cell division, and the level ratio (of heteroplasmy) determines if that person has/doesn’t have a mito. genetic disease
heteroplasmy above the threshold = disease and below = no disease
Describe the rules of maternal inheritance as it relates to mitochondrial disease
a person’s mito are ALL inherited from the mother, bc sperm do not contribute their mito to the zygote (only their DNA)
this means that a father with mito. genetic disease cannot pass it to his children, only mothers can
Describe the threshold concept and its relationship to mitochondrial genetic disease
if a pt’s percentage of mutant mito to normal mito reaches or surpasses the the threshold, then they will develop a mito. genetic disease
How many genes does the mitochondrial genome include? how many of those code for proteins?
the mitochondrial genome has 37 genes total
13 of them code for proteins
The other 24 code for rRNA and tRNA
State the 2 main characteristics of mitochondrial disorders. These characteristics are due to what?
Clinical variability
age related progression of the disease
Both of these are due to heteroplasmy that decides the time of onset and severity of the disease
ex. 95% mutant mtDNA will develop earlier and more rapidly than 85% mutant mtDNA
What is a mitochondrial myopathy?
a muscle disease caused by mitochondrial dysfunction
List the 4 mitochondrial myopathies (include the honorable mention one as well)
MERRF: myoclonus epilepsy with ragged red fibers
MELAS: mitochondrial encephalopathy lactic acidosis and stroke-like episodes
KSS: Kearns-Sayre Syndrome
CPEO: Chronic progressive external opthalmoplegia
(honorable mention)
LHON: Leber hereditary optic neuropathy
(it is honorable mention because muscle is not affected by it, it causes blindness in late adolescence)
List the clinical characteristics of mitochondrial myopathies
Lactic acidosis
Exercise intolerance
Muscle weakness
Other
Neurological signs (encephalopathies)
“LEMON”
define ragged red fibers
aggregates of abnormal mitochondria that form red sarcolemmal blotches
(commonly found in mitochondrial myopathies)
Describe the mutation rate of mitochondrial DNA (mtDNA) and the types of tissues that are most commonly affected by mitochondrial genetic diseases
mtDNA has a very high mutation rate
neurological and muscle tissue are the most affected (bc they require lots of mito to provide energy)
ex. Brain/CNS, Heart, skeletal muscle
what proportion of a mature egg cell’s genome is composed of mtDNA?
1/3rd
how many proteins construct the mitochondrial respiratory chain? how many total complexes are involved in mitochondrial respiration?
87 proteins
5 total complexes
Describe what complexes I through V are involved in and what type of DNA encodes for each of them. (include why complex V is important)
Complexes I through IV are enzyme complexes involved in the E.T.C. that serve to oxidize NADH and FADH2
Complex V is an ATP synthase that uses the H+ gradient (created by the E.T.C.) to create ATP from ADP
Complexes I through V are encoded by both nuclear DNA and mtDNA
List 4 distinctive characteristics of mtDNA, compared to nuclear DNA
It has no DNA repair mechanisms
there is no recombination of the mtDNA
mtDNA has a 10 times higher mutation rate
mtDNA is maternally inherited
state the 2 major divisions of causes of mitochondrial mutations and the respective diseases that are caused by each (2 diseases per cause)
point mutations in mtDNA tRNA genes: cause MELAS and MERRF
mtDNA genome deletions and rearrangements: cause KSS and CPEO
The following are clinical features of what mitochondrial myopathy?
involuntary jerking epilepsy ataxia RRF's in skeletal muscle seizures
MERRF (myoclonus epilepsy with RRF’s disease)
The following are clinical features of what mitochondrial myopathy?
Seizures (stroke-like episodes of hemiparesis (weakness of one side of the body)) Blindness Headaches Anorexia Recurrent vomiting Lactic acidosis RRF's in skeletal muscle
MELAS (mitochondrial encephalopathy lactic acidosis and stroke-like episodes)
The following are clinical features of what mitochondrial myopathy?
Retinitis pigmentosa (degenerative eye disease leading to blindness) At least one of the following (Cardiac conduction abnormality, Cerebellar ataxia, and Cerebral spinal protein level above 100 mg/dL) optic atrophy hearing loss dementia seizures cardiomyopathy lactic acidosis RRF's in skeletal muscle
KSS (Kearns-Sayre Syndrome)
The following are clinical features of what mitochondrial myopathy?
mild to moderate RRF’s in skeletal muscle
Ptosis
CPEO (Chronic progressive external opthalmoplegia)
The following are clinical features of what mitochondrial myopathy?
acute, subacute, bilateral, central vision loss
degeneration of the retinal ganglion cell layer and optic nerve
no muscle issues/myopathies
one eye is initially affected, but it eventually affects both
RRF’s in skeletal muscle
LHON (Leber Hereditary Optic Neuropathy)
LHON is caused by what specific type of mutation of mtDNA and what is it he average age of onset for this disease?
single base pair substitutions in the mtDNA that codes for complex I proteins (normal complex I should have 7 subunits)
the average age of onset is in the 20s to 30s
90% of MERRF cases are caused by __ mutations of _____
2
tRNA lys
85% of MERRF cases are due to __ to __ mutation in the mtDNA tRNA-lys gene at nucleotide position ____
A
G
8344
5% of MERRF cases are due to __ to __ mutation in the mtDNA tRNA-lys gene at nucleotide position ____
G
C
8356
