Human mitochondria

J Neurol Neurosurg Psychiatry74:1188

Endosymbiotic

evolution

Mitochondria arose from proteobacteria

and chloroplasts - from

cyanobacteria.

Nature Rev Gen 5: 123, 2004

Consequences of the

mitochondrial dysfunction

NEJM 1995

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)

J Neurol (2003)

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?)

Lancet 2004

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.

http://jmg.bmjjournals.com

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

Brain 2004

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!

EPIGENETICS..

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.

link

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).

NEJM 349:2042

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

NEJM 349:2042

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.

Nature Rev Gen

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.

source

sou

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

Hum Mol Gen 2003

Prader-Willi

Syndrome:

phenotype

Am J Med Gen

http://health.allrefer.com/

75% of the patients have large

chromosomal deletions of +/- 4

Mb of 15q11-13 region, Always,

the deletion is on the

paternally inherited

chromosome.

sou

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

http://www.asclepius.com/

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

Ann Rev 2001

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