Block D Lecture 1: Single Gene Disorders Flashcards
What are mendelian disorders?
Disorders caused by one gene, where a single mutation in said gene leads to the condition (e.g Huntington’s), they are almost always familiarly inherited and are diagnosable and predictive.
(Slide 3)
What are complex genetic disorders?
Genetic disorders which involve the complex interplay of 2 or more genes. Multiple mutations need to be acquired in order to develop these conditions. These conditions can either be familiarly inherited or sporadic.
(Slide 4)
Why do we need to identify genes responsible for hereditary conditions / diseases?
As finding the genes may allow an understanding of the biological processes involved and how they are going wrong, which could lead to treatments, cures or gene therapy, or could give us opportunities to diagnose or predict illness before symptoms present, or even before birth
(Slide 7)
What 4 things are always required in order to identify the gene which is mutated in the simple genetic order being studied, regardless of method?
DNA samples from the patient, family, general population and healthy controls
(Slide 10)
What are 3 methods which can be used in order to identify the gene containing the mutation leading to the simple genetic disorder being studied?
- Chromosomal damage which can indicate location of mutated gene
- Positional cloning (genetic + physical mapping)
- Sequence the whole genome (exome) of a patient and look for causative mutations
(Slide 10)
How can visible chromosomal damage in patients help us figure out the location of a gene which causes a genetic disorder?
As the damage is thought to be responsible for disrupting or deleting the gene, and these points of chromosomal damage (called breakpoints) can be mapped to try and estimate the location of the gene
(Slide 12)
What is Duchenne Muscular Dystrophy?
It’s a severe X-linked recessive disorder, which presents in boys around 3-5 years old with patients showing progressive muscle weakness
(Slide 13)
What gene was identified to be the cause of Duchenne Muscular Dystrophy, and what is this gene responsible for?
The “DMD” gene which encodes a protein called dystrophin, which anchors moving muscle to the solid extracellular matrix (ECM), which stabilises muscles cells during contraction and protects them from mechanical stress. This gene is also protected in the milder Becker Muscular Dystrophy
(Slide 16)
Why is positional cloning not used any more?
As since it was introduced, the human genome project was completed and next generation sequencing was developed
(Slide 18)
What are the 4 steps of positional cloning?
- Identification of large multigenerational families with a history of the disorder, and then carry out pedigree analysis (family tree thingy) and then linkage analysis with genetic markers to map chromosomal locus containing mutated gene
- Isolate overlapping DNA clones from region
- Identify which genes are in this region
- Analyse DNA sequence to determine is mutations which are in patient samples are not found in healthy family members
(Slides 19 - 24)
(Slide 19)
What is Huntington’s disease?
An autosomal dominant disease, where cells die in the basal ganglia and deep cortical layers which can lead to consequences such as dementia, psychosis, loss of cells in motor control region (leading to frequent, random or twitch-like writhing movements), and premature death
(Slide 25)
What gene was identified to be the cause of Huntington’s disorder and what kind of mutation was found to be the cause?
A repeat expansion mutation in the HTT (Huntingtin) gene
(Slide 28)
What are trinucleotide repeat expansion mutations?
Polymorphic repeats of a specific trinucleotide sequence
(Slide 29)
Why can the number of trinucleotide repeats change between generations?
Are they are unstable in meiosis
(Slide 29)
What are the general trends of age of onset and number of expansion repeats between generations of families, which have a history of Huntington’s disorder?
Age of onset becomes lower and the number of expansion repeats becomes higher
(Slide 30)
