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Medical Genetics
07线粒体疾病的遗传
Inheritance of Mitochondrail Diseases
Medical Genetics
The normal 46 chromosomes in
our body are contained in the center
of the cell, which is called the
nucleus. Mitochondria are structures
in the cell located outside of the
nucleus in the cytoplasm, that also
contain genes that are separate from
the ones in the nucleus.
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Mitochondria are extremely small
(from .002-.008 millimeters in length)
rice-shaped structures whose details
can only be seen with the electron
microscope .
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Mitochondria are often called the
“powerhouses” of the cell because
they are the site where sugar is
broken down to release the energy
required for cellular functions.
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Medical Genetics
A cell may have hundreds or
even thousands of mitochondria
depending on the particular cell’s
need for energy. (For example, the
average human liver cell contains
more than a thousand
mitochondria.)
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In addition to containing the
many proteins needed to control the
energy release process, the
mitochondria also contain a small
amount of DNA that is used to direct
the manufacture of thirteen of the
proteins needed for its activities.
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Medical Genetics
Unlike nuclear genes, which are
inherited from both parents,
mitochondrial genes are inherited
only from the mother.
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If there is a mutation in a
mitochondrial gene, it is passed from
a mother to all of her children; sons
will not pass it on, but daughters will
pass it on to all of their children, and
so on.
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The first human disease that was
associated with a mutation in
mitochondrial DNA is called Leber's
Hereditary Optic Neuropathy, or
LHON.
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mtDNA Point
mutations
Cardiomyopath
y
Leber's optic
neuropathy
Leigh's
syndrome
MELAS
MERRF
NARP/MILS
Single deletion
or duplication
Ataxia,
Leukodystrophy
Diabetes:
Maternal
inheritance
Kearns-Sayre
Pearson's
PEO: Sporadic
Multiple deletions
Aging
Myositis
Inclusion body
COX- muscle
fibers
MNGIE
PEO
Wolfram
Depletion of
mtDNA
Infantile
myopathy Fatal
"Later-onset"
AZT treatment
Several types of
mtDNA defect
Deafness
Diabetes
External
ophthalmoplegia
(PEO)
Sporadic
Maternal
Dominant
Recessive
Leigh's
Myopathy
Rhabdomyolysis
Sensory
neuropathy
Systemic disorders
Intense SDH staining
of a muscle fiber with
mitochondrial
proliferation
Medical Genetics
1. Mitochondrial DNA
Mitochondria have some of their
own DNA, ribosomes, and can make
many of their own proteins. The DNA
is circular and lies in the matrix.in
punctate structures called
"nucleoids". Each nucleoid may
contain 4-5 copies of the
mitochondrial DNA (mtDNA).
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To visualize the structure of
mtDNA, the DNA was extracted and
floated on a water surface. Then, it
can be picked up by a plastic coated
grid, and examined in the electron
microscope.
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Mitochondrial circular DNA is shown.
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Human mtDNA is 16,569 bp; encodes a
number of mitochondrial proteins
• Subunits 1, 2, and 3 of cytochrome oxidase
• Subunits 6, 8 of the Fo ATPase
• Apocytochrome b subunit of CoQH2Cytochrome C reductase
• Seven NADH-CoQ reductase subunits
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Mitochondria also have their own
ribosomes and tRNA:
• 22 tRNAs
• rRNAs
16S, 12S, 5S
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2. mtDNA replication
• Both strands of mammalian mtDNA are synthesized
continuously as leading strands.
• Synthesis of the first mtDNA strand proceeds partially,
pauses, and is then completed upon receipt of appropriate
signals. The result is that most mtDNA has D-loops.
• Synthesis of the second strand is initiated after the fork
synthesizing the first strand passes the origin of second
strand synthesis.
• During plastid DNA replication RNA primers are
incompletely excised and replaced. As a result the plastid
genome is a chimeric DNA-RNA molecule. Origins of plastid
DNA replication have been identified.
• Two D-loops are found in plastid DNA.
They represent initiation on opposite
DNA strands.
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Medical Genetics
3. Mitochondrial Inheritance
In mammals, 99.99% of
mitochondrial DNA (mtDNA) is
inherited from the mother. This is
because the sperm carries its
mitochondria around a portion of its
tail and has only about 100
mitochondria compared to 100,000
in the oocyte.
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As the cells develop, more and
more of the mtDNA from males is
diluted out. Hence less than one
part in 104 or 0.01% of the mtDNA is
paternal.
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Medical Genetics
This means that mutations of
mtDNA can be passed from mother
to child. It also has implications if
one does cloning of mammals with
the use of somatic cells. The
nuclear DNA would be from the
donor cell, but the mtDNA would be
from the host cell. This is how Dolly
the sheep was cloned.
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Inheritance
• During fertilization mtDNA is derived only
from the oocyte;
• Maternal inheritance: mtDNA mutations
transmitted only from mother;
• Mutations transmitted to all offspring,
Male & Female;
• Increased Mutant mtDNA in the mothers'
blood increased Frequency of affected
offspring
• Risks of having affected offspring differ
between different mtDNA mutations
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Threshold effect
• % of mutant mtDNAs must be above a
threshold to produce clinical
manifestations
• % of mutant mtDNAs needed to cause cell
dysfunction varies according to tissue
oxidative requirements
• Disease signs especially manifest in
– Tissues with a high energy expenditure:
Dependent on oxidative metabolism
– Specific tissues: Brain, Heart & Muscle
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Mitotic segregation
– % of mutant mtDNAs in daughter cells
can shift at cell division
– Produces rapid changes of genotype
that may lead to crossing of threshold
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Mutation effects
• Often cause deficient function in
respiratory-chain
• Abnormal Oxidative-phosphorylation
enzymes
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Mutation distribution
• Homoplasmic: Similar distribution of
mtDNA mutation in all tissues
• Heteroplasmic: Variable distribution
of mtDNA mutation in different cells
or tissues
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The following diagram shows a family in
which the mother passed the mutation to her
three children, but only the daughters passed it
to subsequent generations.
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Skewed heteroplasmy
– mtDNA mutation surpasses pathogenic
threshold in 1 tissue
– Examples: A3243G may produce only
cardiomyopathy; Myopathy with early
respiratory involvement
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Medical Genetics