Dr. Mohammed Hussein M.B.Ch.B - PowerPoint Presentation

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Dr. Mohammed

HusseinM.B.Ch.B, MSC, PhD, DCH (UK), MRCPCH

Genetics

Lec.2

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Mitochondrial

Inheritance

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Mitochondria

Are cytoplasmic organelles involved in cellular respiration

Have their own chromosomes

This DNA encodes

13 proteins

that are subunits of complexes in the

electron transport

and

oxidative phosphorylation

processes.

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Ovum

(female gamete)

Sperm

(male gamete)

Mitochondria

Mitochondria

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Because a sperm cell contributes no mitochondria to the egg cell during fertilization, mitochondrial DNA is inherited exclusively through females.

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Pedigrees for mitochondrial diseases thus display a distinct mode of inheritance:Transmission of the disease

is only from a female.All offspring of an affected

female

are affected.

None

of the offspring of an affected male is affected.

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The clinical phenotypes of mitochondrial diseases are highly variable.Within the same family, some individuals may express sever symptoms while others may show mild symptoms.

These variations can be explained by:Heteroplasmy

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A typical cell contains hundreds of mitochondria in its cytoplasm. When

a specific mutation occurs in some of the mitochondria, this mutation can be unevenly distributed into daughter cells during cell division: Some cells may inherit more mitochondria in which the normal DNA

sequence

predominates

While

others inherit mostly mitochondria in which the mutated (disease-causing) DNA sequence predominates. This condition is known as heteroplasmy. Variations in heteroplasmy account for substantial variation in the severity of expression of mitochondrial diseases.

Heteroplasmy

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Leber

hereditary optic neuropathy (LHON)Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke (MELAS)

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How to determining the mode of inheritance in a pedigree

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Ask yourself the following questions

Does an affected individual have an affected parent?

Does

all

affected

are males?Is there male-male transmission?Are all daughters of an affected male also affected?

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Does an affected individual have an affected parent?

Yes: Dominant diseaseNo: Recessive disease

If it is

recessive

, then ask:

Does all affected are males?Yes: X-linked recessive diseaseNo: Autosomal recessive diseaseIf it is dominant, then ask:

Is there male-male transmission?

Yes: autosomal dominant disease

No

: may be an X-linked dominant

Are all daughters of an affected male also affected?

Yes: X-linked dominant

No: autosomal dominant disease

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Autosomal Dominant

Does an affected individual have an affected parent?

Yes

Is there male-male transmission?

Yes

Dominant

Autosomal

Does an affected individual have an affected parent

?

If it is

recessive

, then ask: Does

all

affected

are males?

If it is

dominant

, then ask: Is

there male-male transmission?

Are

all daughters of an affected male also affected?

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Autosomal

Recessive

Does an affected individual have an affected parent?

No

Does all affected are males?

No

Recessive

Not X linked

Autosomal

Does an affected individual have an affected parent

?

If

it is

recessive

, then ask: Does all

affected

are males?

If

it is

dominant

, then ask: Is there male-male transmission?

Are

all daughters of an affected male also affected?

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X-Linked Recessive

Does an affected individual have an affected parent?

No

Does all affected are males?

Yes

Recessive

X linked

Does an affected individual have an affected parent

?

If

it is

recessive

, then ask: Does all

affected

are males?

If

it is

dominant

, then ask: Is there male-male transmission?

Are

all daughters of an affected male also affected?

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X-Linked

Dominant

Does an affected individual have an affected parent?

Yes

Is there male-male transmission?

No

Dominant

May be Autosomal

May be X-linked

Are all daughters of an affected male also affected?

Yes

X-linked

Does an affected individual have an affected parent

?

If

it is

recessive

, then ask: Does all

affected

are males?

If

it is

dominant

, then ask: Is there male-male transmission?

Are

all daughters of an affected male also affected?

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Autosomal Dominant

Does an affected individual have an affected parent?

Yes

Is there male-male transmission?

No

Dominant

May

be Autosomal

May be X-linked

Are all daughters of an affected male also affected?

No

Not X-linked

Does an affected individual have an affected parent

?

If

it is

recessive

, then ask: Does all

affected

are males?

If

it is

dominant

, then ask: Is there male-male transmission?

Are

all daughters of an affected male also affected?

Please stop the video for awhile and try to solve it by yourself

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Pedigrees for mitochondrial diseases display a distinct mode of inheritance

:All offspring of an affected female are affected.None of the offspring of an affected male is

affected.

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Does an affected individual have an affected parent?

YES

NO

Recessive

Dominant

Does all affected are males?

NO

YES

Autosomal Recessive

X-linked Recessive

Is there male-male

NO

YES

Autosomal Dominant

May be X-linked Dominant

Are all daughters of an affected male also affected?

YES

X-linked Dominant

NO

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Important principles that can characterize single-gene diseases

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Important principles that can characterize single-gene diseases

Variable expression

Incomplete penetrance

Pleiotropy

Locus heterogeneity

New mutations

Delayed age of onset

Anticipation

Imprinting

Uniparental disomy

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Variable

Expression

Most

genetic diseases vary in the degree of phenotypic expression:

Some

individuals may be severely affectedWhereas others are more mildly affected

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Variable

Expression

This

can be the result of several factors:

Environmental Influences:

Example: xeroderma pigmentosum Allelic Heterogeneity: Example: missense mutations in the factor VIII gene tend to produce less severe hemophilia than do nonsense mutations.Heteroplasmy

in mitochondrial pedigrees.

Modifier

Loci

Disease

expression may be affected by the action of other loci, termed modifier loci. Often these may not be identified.

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Incomplete Penetrance

A

disease-causing mutation is said to have

incomplete penetrance

when some individuals who have the

disease genotype do not display the disease phenotype.

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Pleiotropy

Pleiotropy exists when a single disease-causing mutation affects multiple organ systems

.

Pleiotropy

is a common feature of genetic diseases.

Marfan syndrome provides a good example of the principle of pleiotropy

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Marfan syndrome

Yao Ming

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Locus Heterogeneity

Locus

heterogeneity exists when the same disease phenotype can be caused by mutations in

different loci

.

For example, retinitis pigmentosa has autosomal dominant, autosomal recessive, and X-linked origins.

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New

Mutations

In

many genetic

diseases, a

large proportion of cases are caused by a new mutation transmitted from an unaffected parent to an affected offspring. There is thus no family history of the disease

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Delayed Age of

Onset

Many

individuals who carry a disease-causing mutation do not manifest the phenotype

until later in life

. This can complicate the interpretation of a pedigree because it may be difficult to distinguish genetically normal individuals from those who have inherited the mutation but have not yet displayed the phenotype.Example: Familial breast cancer

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Genetic Anticipation

Anticipation refers to a pattern of inheritance in which individuals in the

most recent generations

of a pedigree develop a disease at an earlier age or with greater severity than do those in

earlier generations

. For a number of genetic diseases, this phenomenon can be attributed to the gradual expansion of trinucleotide repeat polymorphisms within or near a coding gene.

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Imprinting

Imprinting refers to the fact that a small number of genes are transcriptionally active

only when transmitted by one of the two sexes.

The

homologous locus in the other parent is rendered

transcriptionally inactive. Thus, for imprinted loci, it is normal to have only the maternal (for some loci) active, or only the paternal (for other loci) active.

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On rare occasion, the transcriptionally active gene may be deleted from the chromosome during gametogenesis. This leaves the offspring with no active gene at that locus.

The gene from one parent is inactivated due to normal imprinting, and the gene from the other parent deleted by a mutation. This situation may result in a genetic disease.

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Prader-Willi Syndromeand Angelman Syndrome

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Deletion in Maternal chromosome 15

Angelman syndrome

Deletion in

Paternal

chromosome 15

Prader-Willi

syndrome

P

aternal

P

rader

M

aternal

Angel

m

an

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Uniparental

Disomy

Uniparental disomy

(UPD)

is a rare condition in which both copies of a particular chromosome are contributed by one parent.

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Maternal Uniparental Disomy

(Maternal UPD)

Paternal Uniparental Disomy

(Paternal UPD)

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P

aternal chromosome is deleted

P

rader-Willi syndrome

M

aternal chromosome is deleted

Angel

m

an syndrome

Maternal Uniparental Disomy

(Maternal UPD)

Paternal Uniparental Disomy

(Paternal UPD)

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Dr. Mohammed

Hussein

M.B.Ch.B

, MSC, PhD, DCH (UK), MRCPCH