ALS 7: Phenotypic Variability Flashcards
What has been an issue with classifying diseases in the past?
Often similar symptoms grouped together to classify a disease, leading to conditions with different causes, presenting as similar symptoms being labelled the same disease
How may symptoms actually present between people with the same causal genetic disease?
Differently - different severities of symptoms, different course of the disease
How are diseases classified now?
With different subtypes e.g. 9 subtypes of osteogenesis imperfect (OI)
What are the 4 main things that can affect the phenotype of the same genetic (causal) disease?
- The effect of the environment
- The effects of other genes
- Different mutations in the same gene
- Unstable mutations
What is meant by ‘environment’ (in tha the genes and environment interact with each other)?
Factors external to the person
How can the environment affect the prognosis (likely course of a medical conditon) of a disease?
The gene may make one more susceptible to getting a condition e.g. mutations in the MEN1 gene, a tumour suppressor, can lead to adenomas in the endocrine tissue; and is inherited as autosomally dominant
Some may develop this cancer early, or later, or never, depending on a secondary event e.g. a stressor
Examples of where environmental factors can worsen common diseases?
e.g. polluted air can worsen cystic fibrosis or asthma
What is hereditory haemochromatosis, and why do only 10% of the people with the condition have a clinically relevant iron accumulation?
Autosomal recessive disorder
Mutation in the human homeostatic iron regulator protein (HFE)
Causes dietary iron to be absorbed in excess
Women’s menstrual bleeding can keep the condition under control, and for men, controlling diet (i.e. reduced iron intake) and exercise can also keep the condition under control - leads to better disease prognosis
How can other genes affect a particular genetic disease?
They can interact with the gene causing the disease, making the condition better or worse
An example where the severity of symptoms and prognosis of a genetic disease is affected by other genes?
e.g. The risk of developing infections in patients with cystric fibrosis is partly genetic, certain genes can make a person more susceptible to specific infections
How can different types of mutations in the same gene affect phenotype?
Some may cause a frameshift affecting every amino acid after the point of mutation, others may only cause the removal a single amino acid etc.
e.g. There are two types of muscular dystrophy - Duchenne and Becker
Both are mutations in the dystrophin gene, however, DMD is a frameshift deletion causing no active dystrohpin to be produced, whereas BMD causes the production of a shorter but active dystrophin protein
DMD = mean age of diagnosis is 4.6 yrs, wheelchair dependency by 10 yrs, death at the median age of 17
BMD = (more mild) onset at around 12 yrs, death usually in their 40s / 50s
What is a common type of unstable mutation?
Trinucleotide repeat disorders - trinucleotide repeat expansion
A mutation in which a region of three repeated nucleotides in the genome increases in number during DNA replication
Up to how many trinucleotide repeats keeps the protein it codes for normally functioning, and what happens when there are more repeats?
Generally, fewer than 27 repeats
The more repeats, the closer to the thresehold it reaches, above which they are no longer stable during DNA replication and the repeats increase during subsequent rounds of replication
This changes the protein function and a greater number of repeats results in a more severe phenotype
What is a common example of a disease affected by unstable DNA?
Huntington’s Disease
Caused by the CAG trinucleotide repeat
27 repeats or less = normal
27-34 repeats = minor effects
35-39 = characteristic phenotype, but not all carriers will be affected
40+ = Huntington’s disease in all carriers
What features can help determine whether the variation in the phenotype of the same disease is caused by which / any of the 4 characteristics?
If they are genetically identical, likely to be due to environmental factors only
If they are related, e.g. family members, likely to be environment / interaction with other genes
If they are unrelated, likely to be different mutations in the same gene or variation in trinucleotide repeats
