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Chapter 6
Mitochondrial Inheritance
55
VII. MITOCHONDRIAL INHERITANCE
(Figure 6-1B; see also Chapter 4,
A. Introduction.
In mitochondrial inheritance:
1.
The disorder is observed in
both females and males who have an affected mother
(not the
father).
2.
The characteristic
family pedigree is vertical
in that the disorder is passed from one gener-
ation to the next generation.
3.
There is
maternal transmission only
because sperm mitochondria do not pass into the sec-
ondary oocyte at fertilization, so that the mitochondrial genome of the zygote is deter-
mined exclusively by the mitochondria found in the cytoplasm of the unfertilized second-
ary oocyte.
4.
A
range of phenotypes is seen in affected females and males
because the proportion of mito-
chondria carrying an mtDNA mutation can differ among somatic cells (called
hetero-
plasmy
) and because mitochondria segregate in daughter cells independently of nuclear
chromosomes.
5.
Mitochondria are the only cytoplasmic organelles in eukaryotic cells that show an inheri-
tance independent of the nucleus (
extranuclear inheritance
). The genes located on the cir-
cular mitochondrial chromosome have an exclusively maternal transmission pattern,
whereas genes located on nuclear chromosomes have Mendelian inheritance patterns.
B. Genetic Risk Assessment (see also Chapter 4, Table 4-2).
The genetic risk associated with a
mitochondrial disorder is as follows:
1. Example 1: Affected mother and normal father.
There is a
100% chance
of having an affected
daughter with a range of phenotypes. There is a
100% chance
of having an affected son
with a range of phenotypes.
2. Example 2: Normal mother and affected father.
There is a
0% chance
of having an affected
daughter. There is a 0% chance of having an affected son.
VIII. EXAMPLES OF MITOCHONDRIAL DISORDERS
■
In general, mitochondrial disorders show a wide degree of severity among affected indi-
viduals. This variability is caused, in part, by the mixture of normal and mutant mtDNA
present in a particular cell type (called
heteroplasmy
).
■
When a cell undergoes mitosis,
mitochondria segregate randomly
to the daughter cells.
This means that one daughter cell may receive mostly mutated mtDNA and the other
daughter cell mostly normal mtDNA. The larger the population of mutant mitochondria,
the more severe the disorder will be.
■
Mitochondrial disorders show a
threshold level
where a critical level of mutated mito-
chondria must be reached before clinical symptoms appear. A woman who has not
reached the threshold can still have affected children.
■
Cells that have a
high requirement for ATP
(e.g., neurons and skeletal muscle) are more
seriously affected by mitochondrial disorders. Mitochondrial disorders include the fol-
lowing:
A. mtDNA-associated Leigh Syndrome (mtDNA-LS).
1.
mtDNA-LS is a mitochondrial genetic disorder most commonly caused by a mutation in
the
MT-ATP6 gene
for the
F
o
ATP synthase 6 subunit
whereby a T S G transition occurs at
nucleotide position 8993 (T8993G),
which changes a highly conserved leucine to an arginine
(L156R), or a T S C transition occurs at
nucleotide position 8993 (T8993C),
which changes a
highly conserved leucine to a proline (L156P).
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56
BRS Genetics
2.
A hypothesis is that these amino acid changes in the F
o
ATP synthase 6 subunit block pro-
ton (H
ion) translocation from the intermembrane space to the mitochondrial matrix
and thereby block ATP synthesis.
3. Prevalence.
The prevalence of mtDNA-LS is 1/140,000.
4. Clinical features include:
hypotonia, spasticity, movement disorders, cerebellar ataxia,
periphery neuropathy, signs of basal ganglia disease, hypertrophic cardiomyopathy,
raised lactic acid concentration in blood and cerebrospinal fluid, death occurs by 2 to 3
years of age, and onset occurs at 3 to 12 months of age, often following a viral infection.
B. Mitochondrial myopathy, Encephalopathy, Lactic Acidosis, and Stroke-like Episodes Syndrome
(MELAS).
1.
MELAS is a mitochondrial genetic disorder caused by a mutation in the
tRNA
Leu
gene
whereby an A S G transition occurs at
nucleotide position 3243 (A3243G).
2.
The mutated tRNA
Leu
causes a reduction in the amount and the aminoacylation of the
mutated tRNA
Leu
, a reduction in the association of mRNA with ribosomes, and altered
incorporation of leucine into mitochondrial enzymes.
3.
Mitochondrial enzymes with a large number of leucine residues will have a low probabil-
ity of being completely synthesized. In this regard, cytochrome oxidase (Complex IV) has
been shown to be synthesized at very low rates.
4.
Heteroplasmy is common and expression of the disease is highly variable.
5. Prevalence.
The prevalence of MELAS is 1/6,250 in northern Finland.
6. Clinical features include:
mitochondrial myopathy, encephalopathy, lactic acidosis, and
strokelike episodes.
C. Myoclonic epilepsy with ragged red fibers syndrome (MERRF).
1.
MERRF is a mitochondrial genetic disorder caused by caused by a mutation in the
tRNA
Lys
gene
whereby an A S G transition occurs at
nucleotide position 8344 (A8344G).
2.
The mutated tRNA
Lys
causes a
premature termination of translation
of the amino acid chain
(the amount and the aminoacylation activity of the mutated tRNA
Lys
is not affected).
3.
Mitochondrial enzymes with a large number lysine residues will have a low probability of
being completely synthesized. In this regard,
NADH dehydrogenase (Complex I)
and
cytochrome oxidase (Complex IV)
both of which have a large number of lysine residues have
been shown to be synthesized at very low rates.
4.
Heteroplasmy is common and expression of the disease is highly variable.
5. Prevalence.
The prevalence of MERRF is 1/100,000 in northern Finland, 1/400,000 in
northern England, and 1/400,000 in western Sweden.
6. Clinical features include:
myoclonus (muscle twitching), seizures, cerebellar ataxia,
dementia, and mitochondrial myopathy (abnormal mitochondria within skeletal muscle
that impart an irregular shape and blotchy red appearance to the muscle cells, hence the
term ragged red fibers).
D. Leber’s Hereditary Optic Neuropathy (LHON).
1.
LHON is a mitochondrial genetic disorder caused by 3 mtDNA missense mutations, which
account for 90% of all cases worldwide and are therefore designated as
primary LHON
mutations.
2.
The primary LHON mutations include the following:
a.
A mutation in the
ND4 gene
(which encodes for subunit 4 of NADH dehydrogenase;
Complex I) whereby an A S G transition occurs at
nucleotide position 11778 (A11778G).
This is the most common cause (
50% of all LHON cases) of LHON.
b.
A mutation in the
ND1 gene
(which encodes for subunit 1 of NADH dehydrogenase;
Complex I) whereby a G S A transition occurs at
nucleotide position 3460 (G3460A).
c.
A mutation in the
ND 6 gene
(which encodes for subunit 6 of NADH dehydrogenase;
Complex I) whereby a T S C transition occurs at
nucleotide position 14484 (T14484C).
3.
All 3 primary LHON mutations
decrease production of ATP
such that the demands of a very
active neuronal metabolism cannot be met and suggest a common disease-causing
mechanism.
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Chapter 6
Mitochondrial Inheritance
57
4.
Heteroplasmy is rare and expression of the disease is fairly uniform. Consequently, the
family pedigree of LHON demonstrates a typical mitochondrial inheritance pattern.
5. Prevalence.
Little data exist on the absolute prevalence of LHON. However, the preva-
lence of LHON is 1/33,000 in northern England.
6. Clinical features include:
progressive optic nerve degeneration that results clinically in
blindness, blurred vision, or loss of central vision; telangiectatic microangiopathy; disk
pseudoedema; vascular tortuosity; onset occurs at
20 years of age with precipitous
vision loss; and males are affected far more often than females for some unknown reason.
E. Kearns-Sayre Syndrome (KS).
1.
KS is a mitochondrial genetic disorder caused by
partial deletions of mitochondrial DNA
(delta-mtDNA) and
duplication of mitochondrial DNA
(dup-mtDNA).The partial deletions
of mtDNA have been associated with a marked reduction in the enzymatic activity of
NADH dehydrogenase (Complex I), succinate dehydrogenase (Complex II), ubiquinone-
cytochrome c oxidoreductase (Complex III), and cytochrome oxidase (Complex IV).
2.
Heteroplasmy is common and expression of the disease is highly variable.
3. Prevalence.
The prevalence of KS is not known, although a conservative estimate for the
prevalence of all mitochondrial diseases is 1/8,500.
4. Clinical features include:
chronic progressive external ophthalmoplegia (CPEO; degener-
ation of the motor nerves of the eye), pigmentary degeneration of the retina (“salt and
pepper” appearance), heart block, short stature, gonadal failure, diabetes mellitus, thy-
roid disease, deafness, vestibular dysfunction, cerebellar ataxia, and onset occuring at
20 years of age.
F. Other Common Diseases.
Mitochondrial mutations are also involved in a number of common
human diseases, which include sensorineural deafness. The MELAS mutation is associated
with some cases of noninsulin dependent diabetes, Alzheimer disease, Parkinson disease,
and hypertrophic cardiomyopathy.
IX. SELECTED PHOTOGRAPHS OF MITOCHONDRIAL INHERITED
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t a b l e
6-1
Genetic Disorders Involving Mitochondria
Genetic Disorder
Gene/Gene Product
Clinical Features
mtDNA-associated Leigh
MT-ATP6 gene/F
o
ATP synthase
Hypotonia, spasticity, movement disorders, cerebellar
syndrome (mtDNA-LS)
6 subunit
ataxia, periphery neuropathy, signs of basal ganglia
disease, hypertrophic cardiomyopathy, raised lactic
acid concentration in blood and cerebrospinal fluid,
death occurs by 2–3 years of age, and onset occurs
at 3–12 months of age often following a viral
infection
Mitochondrial myopathy
tRNA
Leu
gene
Mitochondrial myopathy, encephalopathy, lactic
encephalopathy lactic
Cytochrome oxidase (Complex IV)
acidosis, and strokelike episodes
acidosis strokelike
is affected
episodes syndrome
(MELAS)
Myoclonic epilepsy with
tRNA
Lys
gene
Myoclonus (muscle twitching), seizures, cerebellar
ragged red fibers
NADH dehydrogenase (Complex I)
ataxia, dementia, mitochondrial myopathy
syndrome (MERRF)
and Cytochrome oxidase
(abnormal mitochondria within skeletal muscle
(Complex IV) are affected
that impart an irregular shape and blotchy red
appearance to the muscle cells, hence the term
ragged red fibers)
Leber’s hereditary optic
ND4 gene/subunit 4 of NADH
Progressive optic nerve degeneration that results
neuropathy (LHON)
dehydrogenase
clinically in blindness, blurred vision, or loss of
ND1 gene/subunit 1 of NADH
central vision; telangiectatic microangiopathy;
dehydrogenase
disk pseudoedema; vascular tortuosity; onset
ND6 gene/subunit 6 of NADH
occurs at
20 years of age with precipitous vision
dehydrogenase
loss; and, affect males far more often than females
or some unknown reason
Kearns-Sayre syndrome
Delta-mtDNA
Chronic progressive external ophthalmoplegia
Dup-mtDNA
(CPEO; degeneration of the motor nerves of the
NADH dehydrogenase (Complex I),
eye), pigmentary degeneration of the retina (“salt
Succinate dehydrogenase
and pepper” appearance) , heart block, short
(Complex II), Ubiquinone-
stature, gonadal failure, diabetes mellitus, thyroid
cytochrome c oxidoreductase
disease, deafness, vestibular dysfunction,
(Complex III), and Cytochrome
cerebellar ataxia, and, onset occurs at
20 years
oxidase (Complex IV) are affected
of age
58
BRS Genetics
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Chapter 6
Mitochondrial Inheritance
59
rRNA genes
tRNA genes
Protein-coding genes
A
Leu
Va
l
Phe
Ile
Gln
Asn
Gys
Tyr
Ala
Ser
Met
Trp
Asp
Ly
s
Thr
Pro
Glu
Leu
Ser
His
Arg
Gly
16s
ND4
ND4L
ND3
CO3
CO2
CO1
23s
ND1
ND2
CYB1
ND5
ND6
ATPsyn6
ATPsyn8
H
s
tr
a
n
d
L stra
nd
Mitochondrial
B
FIGURE 6-1. Mitochondrial genome and family pedigree. (A)
Location of mtDNA genes and their gene products. ND 1,
ND2,ND3,ND4L,ND4, ND5, ND6
genes for the 7 subunits of the NADH dehydrogenase complex CO1, CO2, CO3 genes for
the 3 subunits of the cytochrome oxidase complex ATPsyn 6, ATPsyn 8
genes for the 2 subunits of the F
0
ATPase complex
CYB1
gene for the 1 subunit (cytochrome b)of ubiquinone-cytochrome c oxidoreductase complex Phe phenyalanine
tRNA gene Val
valine tRNA gene Leu leucine tRNA gene Ile isoleucine tRNA gene Met methionine tRNA gene
Trp
tryptophan tRNA gene Asp asparagine tRNA gene Lys lysine tRNA gene Gly glycine tRNA gene Arg = arginine
tRNA gene His
histidine tRNA gene Ser serine tRNA gene Thr threonine tRNA gene Pro proline tRNA gene Glu
glutamic acid tRNA gene Tyr
tyrosine tRNA gene Cys cysteine tRNA gene Asn asparagine tRNA gene Ala alanine
tRNA gene Gln
glutamine tRNA gene 16S 16S rRNA gene 23S 23S rRNA gene. (B) Pedigree of mitochondrial inheri-
tance. Typical pedigree seen in mitochondrial inheritance. Inheritance is matrilineal, with all children of affected mothers
being affected, but not children of affected fathers. Affected fathers do not produce affected siblings.
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