Week 10: Diseases & syndromes Flashcards
Week 10 Diseases & syndromes
Following this lecture, you should be able to:
- List examples of disease and syndromes that are caused by genetic abnormalities
- Recognise the different type of genomic abnormality that lead to these diseases
- Understand how genetic abnormalities give rise to each disease
- Explain how the link was found between genetic differences and each disease
When people talk about genetic defects, people are generally talking about missing chromosomes or addition of chromosomes
Such as?
Down syndrome & turner syndrome
Down syndrome
What is DS caused by?
What is its prescence?
What increases risk?
What are the symptoms?
Most often caused by the presence of a third copy of all or part of chromosome 21, Downs syndrome = additional copy of chromosome, present in1 in 700 live human births, most common chromosomal abnormality: 1 in 700 live births – although it is a genetic defect it is not mutation.
Risk increases with parent age – no other known risk factors
Wide variety of possible symptoms e.g
- Development delay
- Characteristic facial morphology
- Severe mental retardation
Turner syndrome
What is turn syndrome caused by?
What is its prescence?
What increases risk?
What are the symptoms?
Effects women, when female has one complete X chromosome, no known risk factors, not even parent age.
Female with only one complete X chromosome, no known risk factors, not even parent age
Many possible symptoms e.g
- Developmental problems
- Characteristic morphology
- Lack of sex hormones
People still able to survive and live
Alzheimer’s disease
Many people do not realize that it is fatal, and ultimately leads to pre-mature death
What is it?
How long does it last?
What is the cost of treatment?
Form of dementia common in age, typically lasting up to 10 years until death.
A progressive dementia common in age, typically lasting up to 10 years until death. Devastating for sufferers and their families, and very costly for society – purely from a practical point of you if you are going to be looking after people around the clock it is very expensive – massive push to work out how to treat this – a lot of money put into this
Observed changes – phenotype of AD
Gross changes to brain morphology:
Extensive synaptic loss and neuron death.
What are the characteristics of AD?
How is diagnosis done?
What are we looking for?
Plaques are an accumulation of beta-amyloid Abeta protein
Tangles are formed from hyper phosphorylated tau protein
There are certain biochemical things you can see that seem to be indicative
Start to look at these proteins and identify where they are coming from – other kind of thing – in terms of diagnosis cant do it without looking at the brain – looking to biomarkers
Alzheimer’s disease
Are there any known particular SNPs?
What we have been talking about is superficial – a particular SNP has a particular effect on genetic disease
Few things have been found
Early clues
Link between AD and Down Syndrome – almost all Down syndrome suffers will develop AD – this illustrated relationship between AD
What is causing the excess of Ab?
- What produces Ab? à in 1980s Ab peptide sequenced and mapped to APP gene, on chromosome 21q21
In particular when people got a better idea of gene structure in the 1990s; Exon 17 of APP found to be responsible for Ab encoding.
Among patients with early onset AD, association with a GàA transition in this exon was discovered.
Subsequently found to be one of many “gain of function” mutations in APP - increases production of Ab – having multiple (unmuted) copies of APP also found to increase Ab production, and AD risk. This is a so-called “gene dosage” effect
However, APP mutations and duplication are rare – only responsible for a tiny number (0.1%) of AD cases. A particular flavour of early onset AD called AD1.
AD&FTDMDB à
Database with a very long name
Among early onset AD sufferers, did all have APP mutations or duplication?
What other mutations were identified?
Even among early onset AD sufferes, not all had APP mutation or duplication.
In 1992, linkage to chromosome 14q24.3 was discovered à DNA fragments from this region used to detect brain transcripts and differences in transcript sequence between healthy and disease sought.
This led to discovery of a new gene, now known as PSEN1, which if mutated at a specific locus increase Ab production. This type of Alzheimer’s is termed AD3.
Homology search across the genome found PSEN2, a similar gene with similar pathogenic mutations
The ApoE Connection
Where can ApoE be found?
Looking at real samples, Apolipoprotein E (ApoE) found to be a major component of plaques and tangles.
Protein sequencing reveals three isoforms of ApoE:
Strong association found between ApoE epsilon4 and late onset AD (other genetic factors excluded).
Important finding – something from looking at the brain – look back and identify these things
Different studies done on different people in the 1990s
What is showing is that in all of these studies there is an increase in the population of people developing AD – from personal genotyping you can find out your chances of developing it – higher than the average –
ApoE enahcnes Ab breakdown – the e4 variant…
ApoE related AD is called AD13
A complex and developing field
Nature paper: another gene – done a GWAS and seem to have found a relationship between a particular…
Looking across the genome and see some threshold and different proteins have this effect of someone getting AD
This is a typical way in which people do these studies
2009 paper
Second paper nature – 2011 – people working on this all the time
This site is a synopsis for AD
What this shows you is that there is definitely studies done that there is a significant correlation – specific genes and AD – when you start looking at the database…
Difficult to pin down and start looking for a treatment for it
Each of these individual variation seem to account for this
Environmental effects
Genetic variation still only links to about 5% of AD cases.
Numerous chemical interactions inferred…
…but despite many studies, no definitive evidence has been found linking any particular activity or substance to AD
Toxicogenomics databases you can see there is a lot of AD result for chemicals
Fragile X
What is it?
Most common cause of inherited mental retardation
Can also produce morphological abnormalities and symptoms of autism spectrum disorders.
Psoriasis
What is the genetic basis
Not the usual single SNP – basically this is caused by copy number variation – a particular region has been copied more than once, this is due to an unusually high number of copies of chromosomal region 8p23.1. This is known as copy number variation (CNV)
Region in the chromosome – when the DNA is replicated a whole new section is added – similar to the extension of repeats but different mechanism – duplication process
Dosage effect – more copies of the gene that you need the protein present in that gene will be higher dose – keep protein under control – as it psoriasis it doesn’t happen
