Biology 🧬 unit 16.2 i) albinism, haemophilia and sickle cell anaemia

What type of condition is albinism

An autosomal recessive condition that is an example of the relationship between genes, enzymes and phenotype

in albinism what does the TYR gene code for and what does it do

the TYR gene codes for the enzyme tyrosinase, which catalyses the hydroxylation of the amino acid tyrosine to form a chemical known as DOPA

How is the chemical known as DOPA formed (albinism)

the TYR gene codes for the enzyme tyrosinase, which catalyses the hydroxylation of the amino acid tyrosine to form a chemical known as DOPA

what does the TYR gene then catalyse after DOPA is formed (albinism)

It then catalyses the oxidation of DOPA to form dopaquinone, from which the dark pigment melanin is synthesised (in specialised cells known as melanocytes)

Individuals that produce melanin in this way have a phenotype that includes coloured irises of the eyes, as well as hair and skin that are varying degrees of brown and black

On what chromosome is the gene TYR located on

Chromosome 11

What do most mutations of the TYR gene result in

The production of a non-functioning enzyme

In the absence of the enzyme no ……… is produced (Albinism)

Melanin

If the enzyme is absent and no melanin is produced what does this mean about the phenotype

Pale skin, white hair and eyes that appear pink because the red retina is visible through the almost transparent iris

What is the genotype for someone who is albino

homozygous recessive - has thus inherited a recessive allele from both parents

How is haemophilia A caused

It is a sex-linked recessive disorder caused by a mutation in the F8 gene located on the X chromosome

What does the normal allele in haemophilia code for

And where is the protein synthesised

the normal allele codes for a protein that has a role in blood clotting known as coagulation factor VIII or factor VIII

The protein is synthesised in liver cells and is released in an inactive form into the circulation

What does blood vessel injury trigger (haemophilia)

a complex sequence of events known as a coagulation cascade

This involves blood platelets, plasma proteins and coagulation factor proteins such as factor VIII

What does a lack of factor VIII mean (haemophilia)

A lack of factor VIII prevents the activation of the enzyme thrombin, which catalyses the formation of the insoluble protein fibrin, a component of the blood clot

As haemophilia is a sex linked disease mostly …….. are affected

males

What does the enzyme thrombin do (haemophilia)

catalyses the formation of the insoluble protein fibrin, a component of the blood clot

What is the most common mutation for haemophilia

approx. 90% are base substitutions mutations

Depending on the substitution, these mutations will result in a change in a ……… …… ….. (missense mutations), or if the change in the mRNA codon is a STOP codon, a …….. protein (nonsense mutation)

single amino acid

Shortened

Severe haemophilia has been associated has been associated with what proteins

With shortened proteins (from nonsense mutations) that may not be folded or release from the cell into the circulation

Mutations associated with ……… or ………. Result in severe haemophilia

Insertions or deletions

The blood clotting time for individuals with haemophilia is greatly ………

This means abnormal bleeding occurs after events like ……

increased

Eg. Injury, dental treatment or surgery

with the more severe forms of haemophilia there can be slow and continued ……… bleeding, especially in the joints or ………

Internal

Muscles

How can haemophilia be controlled

This disease can be life-threatening but is now controlled by treatment for example with factor VIII produced using recombinant gene technology

This means that people with haemophilia can lead near-normal lives

What type of disorder is sickle cell anaemia

An autosomal disorder

What is sickle cell anaemia the result of

A single base substitution mutation in chromosome 11 in the HBB gene coding for the beta-globin polypeptide of the globular protein molecule, haemoglobin

Outline how a single base substitution leads to sickle cell anaemia

• The 6th DNA triplet is changed with a thymine replacing an adenine → on the non-template strand GTG replaces normal GAG → on the template (transcribed) strand CAC replaces normal CTC

• The 6th codon of mRNA transcript has the codon GUG, for valine, rather than GAG for glutamic acid

• The sixth amino acid of the beta chain now has valine, which has a hydrophobic R-group instead of glutamic acid which has a polar R group - this minor change in the primary structure of the beta chain changes the tertiary and quaternary structure of the haemoglobin molecule

• The change causes the loss of the globular shape of haemoglobin and it becomes less soluble

• This produces a molecule of haemoglobin-S that has a ‘sticky patch’, so that when the haemoglobin molecules are not carrying oxygen (ie. At low oxygen concentrations) they tend to adhere to one another by their sticky patches and form long fibres within the red blood cells. The affinity of haemoglobin for oxygen is greatly reduced

• These fibres distort the red blood cells, making them less flexible and sickle (crescent) shaped

Sickle cell anaemia 1: the HBB gene (coding for the beta-globin polypeptide) coding for the chain has a mutation where what happens?

the base thymine replaces adenine on its non-template strand

Sickle cell anaemia 2: the mRNA produced has what triplet codon

The mRNA produced has the triplet codon GUG (for amino acid valine) rather than GAG (for amino acid glutamic acid)

Sickle cell anaemia 3: the beta-globin polypeptide chain produced has one ………… acid replaced by a …….

glutamic

Valine

Sickle cell anaemia 4: the haemoglobin molecules containing the abnormal beta chains become sticky and clump to from long fibres when the oxygen level …. ….. …… … ….

This haemoglobin is called ……….

of the blood is low

Haemoglobin-S

Sickle cell anaemia 5: the haemoglobin-S molecules within the red blood cell causes the shape of the cell to become what?

crescent (sickle) shaped

Is sickle cell anaemia life threatening?

Yes

Haemoglobin-S is less efficient at what?

carrying oxygen → the patient therefore suffers anaemia → life threatening

The sickle cells may block what and what does this mean?

the sickle cells may block blood vessels, depriving organs of oxygen and permanently damaging them → life threatening

What happens if sickle cells block capillaries

The supply of oxygen to tissues and organs is reduced

The blockages caused by sickle cells can cause pain

How does the life-span of a sickle cell compare to that of a normal cell

Sickle cells have a short life span of 10-20 days compared to the lifespan of normal red blood cells of 120 days, and large-scale removal can result in anaemia (haemolytic crisis)

The lack of red blood cells in anaemia causes tiredness and inactivity as there is not enough oxygen transported to body tissues

What can a lack of red blood cells in anaemia cause?

tiredness and inactivity as there is not enough oxygen transported to body tissues

What are the 3 different genotypes and their results in the three different phenotypes for sickle cell anaemia

Hb^A Hb^A (normal)

Hb^S Hb^S (sickle cell anaemia)

Hb^A Hb^S (sickle cell trait)

This is an example of codominace - heterozygous individuals are generally symptomless except when the oxygen concentration of their blood is low eg. In exercising muscles, when the abnormal haemoglobin makes the red blood cells sickle shaped and less able to carry oxygen, leading to tiredness