Genetics in Medicine (History) Flashcards
What are the symptoms of sickle cell anaemia?
Anaemia, fever, sever pain often accompanied by sudden death
What is the molecular basis of of sickle cell?
Sickle cell is caused by a single base mutation from an A to a T in the beta-globing chain. This causes a change in the beta-globin protein at position 6 in the amino acid chain from GLUTAMATE to VALINE.
What inheritance pattern does sickle cell show?
Sickle cell anaemia is autosomal recessive inheritance so, you need both copies of the gene to get the disease. However, individuals that are heterozygous for the mutation have a mild form called sickle cell trait.
Where is sickle cell anaemia most common? Why?
Sickle cell is common in African populations and people with recent African ancestry but rare everywhere else in the world. This is because individuals who are heterozygous for the mutation are resistant to severe malaria (caused by Plasmodium falciparum)
How could epigenetic therapy be used as a cure for sickle cell?
Foetal (gamma) global is turned off after birth and adult (beta) global is turned on. If gamma globin was kept switched on, the you would have less beta subunits (with the mutation) which would mean sickle cell would be less severe.
How could the gamma globin gene stay switched on?
Protein BCL11A is a repressor, it binds to the DNA and switches off the gamma globin gene.
In mice with the BCL11A gene deleted, gamma globin is kept switched on after birth. This has the potential (although it doesn’t happen yet) to be targeted by drugs in humans. Persistence of foetal haemoglobin is not harmful so, keeping gamma globin switched in could work…
How can gene editing therapy be used as a cure for sickle cell.
Isolate haemopoetic stem and edit the GTG back to GAG. This forms the normal B-globin gene. You then engraft it in the bone marrow to form normal red blood cells.
What system is used for gene therapy?
CRISPR system. An RNA guide is gyntheised and targeted against DNA you want to change. CAS9 (an enzyme) can be attached to guide to find the target DNA. This attaches and cuts both DNA strands. DNA cuts can be amended with a DNA insertion or a deletion of defective DNA.
What is huntington’s disease?
This is an inherited neurogenerative disease. It is characterise by:
Seizures, abnormal gait (mannor or walking), personality changes and dementia.
What inheritance pattern does huntington’s disease show?
Huntingtons is autosomal dominant.
What is the avg age of onset of Huntington’s?
The ago of onset is commonly 40-50 but it can vary between childhood and very old age. From generation to generation the age of onset becomes earlier and the symptoms because more severe. This is called ‘Anticipation’.
The age of onset is also affected by the number of CAG repeats (more repeats = earlier age of onset) but, still A LOT of variation.
There are also other genetic factors involved eg one on chromosome 8 and two on chromosome 15 (but yet to identify the actual genes).
What is a possible treatment for huntington’s disease?
Suppressor screening. This is when you identify every gene in turn and identify genes that, when deleted, prevent Huntington’s.
How do you do suppressor screening?
You delete the gene and then insert CAG into a plasmid. If the plasmid survives then the gene is a suppressor. This can be done in yeast, flies and in mice. (need to inhibit the kynurenine metabolic pathway).
What is a de novo mutation?
De novo mutation, an alteration in a gene that is present for the first time in one family member as a result of a mutation in a germ cell (egg or sperm) of one of the parents or in the fertilized egg itself
