The Genetic Basis of Disease

Affected het

Dominant phenotype

Unaffected het

Recessive phenotype

Example of dominant inheritance

Achondroplasia

Achondroplasia

Mutation of the FGF receptor. It is usually turned off however in achondroplasia is it always turned on.

Example of recessive inheritance

Phenylketonuria

Phenylketonuria

Results from deficiency of phenylalanine hyroxylase - enzyme that catalyses the hyroxylation of phenylalanine to tryosine.

Why are males more likely to be colour blind than females?

Because the red and green opsin genes are on the X chromosome, and males have only one X; any mutation in their single R or G opsin gene causes colour blindness, whereas females have two X chromosomes so a normal allele usually compensates.

Sickle cell disorder

• Caused by a mutation in the gene encoding beta-globin

• Under low O₂ conditions, HbS (haemoglobin sickle) forms long aggregates which distort the shape of RBCs

• Affected cells can’t pass through narrow blood vessels, leading to a sickling crisis.

How does sickle cell gene therapy work?

1. Stem cells are extracted

2. Stem cells are genetically modified

3. These cells are re-injected to the patient

4. Stem cells make halethy foetal haemoglobin and normal RBCs

SMA

• Caused by mutations in the SMN1 gene

• Severe neuromuscular disorder - death of motor neurones and progressive muscle wasting

Gene therapy for SMA

Nusinersin blocks SMN2 exon 7 skipping so more functional SMN2 protein made which can compensate for loss of SMN1 function

Penetrance

The frequency with which a genotype manifests itself in a given phenotype.

λ

The risk ration - the higher the number, the more cloesely related the group is to the person with disease (increasing indicates increased risk)

Monogenic

Caused by mutation in a single gene

Polyphagia

Abnormally strong, incessant sensation of hunfer or desire to eat

Its not a disorder itself but a sympton indication an underlying medical condition

Single nucleotide polymorphism (SNP)

Locus where different individuals have a different DNA base in their genomic sequence.

Generally a disease associated SNP does not directly cause the disease

Germline

The germ cells (gametes) and those that give rise to them

Can be passed onto subsequent generations

Somatic cell

Any cell in the body that is not part of the germline

Cannot be passed on through generations

Oncogenes

• Promote cell division

• When mutated in cancers, usually have a dominant effect

Tumour suppressor genes

• Inhibit cell division, protect against DNA damage

• When mutated in cancers, usually have a recessive phenotype

What type of mutation converts a proto-oncogene into an oncogene?

A dominant gain of function mutation

What type of mutation inactivates tumour suppressor genes?

a recessive loss of function mutation

Why do tumour suppressor gene mutations act recessively?

Both gene copies must be inactivated to lose function

Knudson’s two hit hypothesis

In order for a particular cell to become cancerous, both of the cell’s tumour suppressor genes must be mutated

What is bcr-abl fusion protein?

A fusion of the bcr and abl genes that creates an abnormally active tyrosine kinase driving tumour cell survival and proliferation leading to cancer such as chronic myeloid leukamia

How does Imatinib (Gleevec) inhibit the bcr-abl fusion protein?

It competitively binds to the bcr-abl kinase domain, blocking substrate access and preventing phosphorylation, which stops tumour cell proliferation