Human mitochondria
J Neurol Neurosurg Psychiatry74:1188
Human mitochondria
J Neurol Neurosurg Psychiatry74:1188
Endosymbiotic
evolution
Mitochondria arose from proteobacteria
and chloroplasts - from
cyanobacteria.
Nature Rev Gen 5: 123, 2004
Mitochondrial disorders –
muscle biopsy
Ragged-red muscle fibers on Gomori stain
http://www.neuro.wustl.edu
Elevated lactate
concentrations in serum
and cerebrospinal fluid –
the main laboratory finding
in mitochondrial disorders
Maternal inheritance
Complicated by variable
pentrance
Relaxed replication of mitochondrial
DNA (mtDNA) and accumulation of
mtDNA mutations leading to
stochastic variation in disease
expression
Lancet 2002
Large (such as
4977 bp)
deletions
in mtDNA
prev. ~1:5 000
1 2 3
4 5
Southern blot hybridized with mtDNA probe
1,2 single deletions, 3,4 – multiple deletions, 5 –
normal mtDNA.
Note heteroplasmy (normal variant is always present)
Large deletions in mtDNA – clinical
picture
Brain 2004
Lancet 2004
mtDNA deletion disorders
with mitochondrial
inheritance: genetic
counselling
• Incidence does not increase with
maternal age
• Unaffected mothers are unlikely to
have more than one affected child.
• Children of affected women have
empirical risk of about 1:24 births (why
not all? –embryonic viability?)
Leber’s hereditary optic
neuropathy (LHON)
• Typically affects young males.
Visual acuity deteriorates over a
period
of
days/weeks
as
a
consequence of rapid, painless loss
of central vision in one eye, usually
followed by the other eye. Stable
residual values at or below 20/200
are reached in a few months,
associated with a large centro-
caecal absolute scotoma.
• Worldwide ~90% patients harbour
one
of
three
mtDNA
point
mutations affecting genes that code
for different subunits of complex I
(11778G>A,
3460A>G
or
14484T>C)
• Typicall
variable
expression
which
may
be
due
to
the
association of pathogenic mutations
with specific mtDNA haplogroups,
environmental factors such as
smoking and a nuclear modifier.
Nuclear genes make a major
contribution to mitochondrial
metabolic systems - role for nuclear
gene mutations in mitochondrial
dysfunction
Mitochondrially encoded subunits (shown in bright color)
vs. nuclear-encoded subunits of respiratory chain
complexes
Niektóre schorzenia
(najczęściej pewne
przypadki PEO)
przebiegające z
delecjami mtDNA
wykazują dziedziczenie
autosomalne
Mutacje w POLG1
u pacjentów z PEO
Mechanizm:
• Zaburzenie polimeryzacji (gł. mutacje dominujące ?).
• Zaburzenie naprawy błędów (gł. mutacje
recesywne ?).
Mutacje w genie
helikazy/dNTPazy ‘Twinkle’
u pacjentów z PEO
Mechanizm:
•
Wzrost aktywności dNTPazy i deplecja
mitochondrialnej puli nukleotydów?
Mutacje w ANT - adenine nucleotide
translokator
(ATP/ADP translokator)
u pacjentów z PEO
Mechanizm:
• Zaburzenia mitochondrialnej puli nukleotydów?
• Związek z funkcją proapoptotyczną (ANT uczestniczy w
tworzeniu MPTP -‘ mitochondrial permeability
transition pore) – wzrost stężenia ROS prowadzący do
uszkodzeń mtDNA
Integralność mtDNA a
starzenie?
Normalna mysz
Myszy z defektem POLG1
Delecje mtDNA
Łysienie
Zanik tkanki podskórnej
Kyfoza
mtDNA - Podsumowanie
• Defekty mitochondriów – bez względu na
przyczynę - dają często zbliżone objawy
• Typowa jest heterogenność fenotypowa
związana ze stochastycznymi procesami
replikacji mitochondriów oraz słabo poznanymi
interakcjami ze środowiskiem i/lub innymi
genami
• Mutacje mtDNA dziedziczą po matce, ale w
szeregu przypadków defekty mitochondriów,
łącznie z pewnymi formami delecji mtDNA, są
skutkiem mutacji genów jądrowych
• Stabilność mtDNA może być istotna w innych
chorobach, a także w procesach starzenia
Imprinting disorders
Effect depends on whether maternal or paternal chromosome is affected.
Specific counselling
Imprinting effects -
example of parental sex-
dependent influence on
phenotype
• mare x donkey =mule,
• stallion x donkey = hinny (shorter
ears, a thicker mane and tail, and
stronger legs than the mule)
Imprinting - the differential expression of alleles depending on the parent of
origin
An imprinting defect is an abnormality of the parent-of-origin-specific gene
regulation, such that a maternal allele or genomic domain has the resulting
pattern of gene expression) of a paternal allele or genomic domain, or vice versa.
Imprinted genes are often differentially methylated!
Genetic imprinting - principles of
inheritance
Idealized pedigrees for maternal and paternal imprinting. These figures are meant to diagram
what a pedigree of human disease that had imprinting effects might look like. The term
"imprinting" implies a modification in expression of a gene or allele. An "imprintable" allele will be
transmitted in a Mendelian manner, but expression will be determined by the sex of the
transmitting parent. In these idealized pedigrees the term "maternal imprinting" is used to imply
that there will be no phenotypic expression of the abnormal allele when transmitted from the
mother, and paternal imprinting is used to imply that there will be no phenotypic expression when
transmitted from the father. Because there will be a phenotypic effect only when the gene in
question or chromosome segment in question is transmitted from one or the other parent, there
are a number of nonmanifesting carriers.
Paternal imprinting
Maternal imprinting
Genetic imprinting
Hum Mol Genet. 1992 Apr;1(1):7-10
Autosomal dominant glomus tumors manifest only when the gene is inherited
from the father (family reported by Heutink et al., 1992
Pathway for the
Methylation of Cytosine in
the Human Genome
A family of three active enzymes, the DNA
methyltransferases (DNMTs), catalyzes the methylation
of the 5 position of the cytosine ring, using S-adenosyl-
methionine as the donor molecule for the methyl group
(CH3).
Methylation is imposed only on cytosines that precede a
guanosine in the DNA sequence (the CpG dinucleotide).
DNA (CG) methylation
A methylating
enzyme
(white) binds
to its target
site (red) on
DNA;
the
methyl donor
is shown in
green
Distribution of CpG Dinucleotide and
Differences in Methylation Patterns between
promoters and the rest of DNA
Life cycle of methylation
imprints
IC -Imprinting control element. Grey indicates modification and
white indicates no modification at the corresponding alleles.
Parental chromosomes are marked according to their sex in blue
(male) or red (female). The reading (transcriptional interpretation
of the primary imprints) in the developing embryo is indicated by
arrows.
Beckwith-Wiedemann
Syndrome
• 1:14 000
• Congenital macroglossia,
exomphalos and gigantism,
danger of neonatal
hypoglycemia and brain damage.
• Increased risk of cancer. Wilms
tumor is the most common (5-
7%). Most cases before fourth
birthday.
Map of the 11p15 imprinted region
affected in Beckwith-Wiedemann
Syndrome
Red -maternally expressed genes,
Blue- paternally expressed genes
.
Gray - not imprinted
.
DMR-differentially methylated region, IGF- insulin like growth factor, CDKN1C -cyclin-
dependent kinase inhibitor (negative regulator of cell proliferation)
25- 50% patients have biallelic expression of IGF2. Another 50% of patients have an
epigenetic mutation resulting in loss of imprinting of a transcript called KCNQ1OT1, 10%
of patients - paternal uniparental disomy (UPD) of 11p15
Prader-Willi
Syndrome:
phenotype
75% of the patients have large
chromosomal deletions of +/- 4
Mb of 15q11-13 region, Always,
the deletion is on the
paternally inherited
chromosome.
Angelman Syndrome
• Developmental delay,
functionally severe
• Speech impairment, none or
minimal use of words;
receptive and non-verbal
communication skills higher
than verbal ones
• Movement or balance
disorder, usually ataxia of
gait and/or tremulous
movement of limbs
• Behavioral uniqueness: any
combination of frequent
laughter/smiling; apparent
happy demeanor; easily
excitable personality, often
with hand flapping
movements; hypermotoric
behavior; short attention
span
• „HAPPY PUPPET”
appearance
70% of the patients have
deletions of +/- 4 Mb in the
15q11-13 region. The deletion is
always on the maternally
inherited chromosome.
Causes for
Prader-Willi
Syndrome (PWS) and Angelman
Syndrome (AS)
Red -maternall chrmosome genes,
Blue- paternall chromosome
No single gene muations.
A polygenic defect?
Imprinting -
podsumowanie
• Forma monoallelicznej ekspresji genu, w
której wyciszeniu ulega kopia od rodzica
zawsze tej samej płci
• Niespójna nomenklatura
• Niejasne pochodzenie ewolucyjne – być
może związane z antagonizmem
płód(ojciec)-matka
• Inaktywacja często (zawsze?) związana z
metylacją DNA
