Mitochondrial DNA
• Mitochondrial genes are inherited exclusively from the
mother(matrilinear).
• Mitochondrial chromosome is ring-shaped.
• No histone beads.
Mitochondrial DNA
● There are 37 genes of
Mitochondrial chromosome.
● 2 rRNAs
● 22 tRNAs
Mitochondrial DNA
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13 subunits of enzymes that are involved in
oxidative phosphorylation.
rRNAs and tRNAs - mitochondria-encoded
polypeptides.
Introns are absent.
only uses DNA polymerase γ.
Mitochondrial DNA
Encephalomypathy
Cardiomyopathy
Myopathy
MELAS
Parkinson’s disease
Hypertension
Hypercholesterolemia
Hypomagnesemia
Motor neuron disease
Sideroblastic anemia
myoglobinuria
MELAS
Leigh
syndome
Diabetes
Deafness
LHON - Leber
hereditary
optic neuropathy
Inheritance patterns of Mitochondrial(cytoplasmic) DNA
• Replicative segregation – random replication, random sorting in
mitosis.
• Homoplasmy – all mutant or all normal
• Heteroplasmy – mixture of mutant and normal DNA
• Maternal inheritance
Inheritance patterns of Mitochondrial DNA - conclusion
•
All children of females homoplasmic for a mutation will inherit the
mutation.
•
the children of males carrying a similar mutation almost always will
not.
•
Females heteroplasmic for point mutations and duplications will pass
them on to all of their children.
•
Respiratory chain mutations are a result of nuclear genome mutations
and mitochondrial genome mutations.
Characteristics of mtDNA
• phenotypic threshold effect – critical threshold has to be reached for
mtDNA mutation diseases to arise.
• mitochondrial genetic bottleneck - restriction and subsequent
amplification of mtDNA during oogenesis
• Variation in syndromes – MELAS -> chronic progressive external
ophthalmoplegia
Mutations in Mitochondrial DNA
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o
o
o
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There are about 200 types of mutations have been identified in mDNA.
The most common types of mutations are:
Point mutations(synthesis disruption),
rearrangement mutations(generate deletion/duplication),
missense mutations(altered activity of enzymes).
Different organs and systems can be affected, but mostly there are
neuromuscular disorders.
• Mutations are prevalent because of the maternal inheritance or somatic
mutations.
• Mutations in noncoding tRNA and rRNA still cause disorders, even
though they do not produce proteins.
Disease
Phenotype
mtDNA
genotype/Mutation
Homoplasmy vs
heteroplasmy
inheritance
MELAS –
Mitochondrial
encephalopathy lactic
acid stroke
Myopathy, encephalopathy lactic
acidosis, stroke-like episodes
Point mutation in
tRNA 3243A>G;
3271T>C/ND5
Heteroplasmic
maternal
Leigh syndrome
Developmental delay optic atrophy
Point mutation in
ATPase subunit 6
gene/ND5
Heteroplasmic
maternal
MERRF - Myoclonic
epilepsy with ragged
red fibers
Myoclonic episodes, myopathy,
ragged-red (muscle) fibers
Point mutation in
rRNA
Heteroplasmic
maternal
Deafness
Sensorineural hearing loss
1555A>G
Homoplasmic
maternal
Neurodegeneration,
Ataxia, and Retinitis
Pigmentosa
night blindness
neurological symptoms
seizures can present at
almost any age
developmental
delay
T > G substitution at
nucleotide m.8993
MT-ATP6
Heteroplasmic
maternal
MERRF
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Multiple mtDNA mutations have been identified in
MERRF.
The most common mutation observed is an A-to-G
mutation at nucleotide 8344 (m.8344A>G)
The lactic acid levels are typically increased in both blood
and cerebrospinal fluid (CSF) in symptomatic as well as
the asymptomatic patients with MERRF.
NARP
Relations between Nuclear genes and Mitochondrial
genes
• Both the nuclear and mitochondrial genomes contribute polypeptides
to oxidative phosphorylation.
• nuclear genes code proteins for mtDNA replication and the
maintenance of its integrity
• For example: autosomally transmitted deletions in mtDNA and
mtDNA depletion syndrome.
Health Conditions Related to Chromosomal
Changes • Kearns-Sayre syndrome
•
Leber hereditary optic neuropathy
•
Leigh syndrome
•
Mitochondrial complex III deficiency
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Mitochondrial encephalomyopathy, lactic acidosis, and
stroke-like episodes
•
Myoclonic epilepsy with ragged-red fibers
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Neuropathy, ataxia, and retinitis pigmentosa
•
Diabetes mellitus and deafness (DAD)
•In the United States: estimated 1000–4000 births
with mitochondrial disorders each year
Cytochrome c oxidase
Cytochrome c oxidase deficiency
Clinically
myopathy
Hypotonia
encephalomyopathy.
Approximately one-quarter of individuals with cytochrome c oxidase deficiency have a type
of heart disease that enlarges and weakens the heart muscle (hypertrophic cardiomyopathy).
Another possible feature of this condition is an enlarged liver (hepatomegaly), which may
lead to liver failure.
Most individuals with cytochrome c oxidase deficiency have a buildup of a chemical called
lactic acid in the body (lactic acidosis), which can cause nausea and an irregular heart rate,
and can be life-threatening.
Kearns-Sayre syndrome
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progressive external ophthalmoplegia
•
pigmentary retinopathy
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cardiac conduction defects
Ataxia
Sensorineural hearing loss
Anemia
Diabetes
Cognitive defects
Leber hereditary optic neuropathy
(LHON):
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Usually presents with bilateral optic neuropathy
(permanent visual loss predominantly in young men)
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Maternally inherited (associated with mtDNA point mutation)
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Other features can include:
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Seizures
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Extrapyramidal syndrome
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Ataxia
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Intellectual disability
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Peripheral neuropathy
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Cardiac conduction defects
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Multisystem disease (variable combination of
manifestations, with Leigh syndrome and
mitochondrial encephalomyopathy, lactic acidosis
and stroke-like episodes (MELAS) as the most
common)
Leigh syndrome
Subacute necrotizing encephalomyelopathy,
often in infancy and early childhood
Pathology: bilateral, symmetric necrotizing
lesions with spongy changes in the basal
ganglia, thalamus, brain stem, and spinal cord
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•
•
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MELAS
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(Mitochondrial
encephalomyopathy,
lactic acidosis and stroke-like episodes):
Varying degrees of cognitive impairment
and dementia
Lactic acidosis
Stroke-like episodes
(hemiparesis, hemianopia, or
cortical blindness)
MERRF syndrome-Ragged Red Fibers"
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Myoclonus
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Epilepsy
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Myopathy
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Ataxia
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Short stature
CT scan of the cervicothoracic giant lipoma in case 1, with an
anteroposterior diameter of 15 cm and a transverse diameter of
30 cm. Axial (A) and sagittal (B) sections.
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Coenzyme Q10 (CoQ10) deficiency:
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Coenzyme Q10 is an important electron carrier, antioxidant, and important factor
in DNA repair and cellular membrane regulation.
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Mitochondrial disorder leads to reduced CoQ10 levels.
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Can present with proximal muscle weakness only (isolated myopathy)
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Can also have ataxia, encephalomyopathy, and nephrotic syndrome
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A 32-year-old woman has a history of recurrent generalized seizures,
diffuse muscular weakness, and multiple episodes of transient left-sided
paresis. She has been hospitalized several times for severe lactic acidosis
requiring intravenous fluid hydration. Her 7-year-old son has occasional
muscle weakness and headaches but has never had a seizure. Pathologic
examination of a biopsy specimen from the woman's soleus muscle shows
ragged-appearing muscle fibers. Genetic analysis of the patient's son is
most likely to show which of the following?
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Heterogenous mitochondrial DNA
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Mutation in DNA repair gene
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Genetically distinct cell lines
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Altered allele on the X chromosome