12,13,14 Flashcards
What is androgenesis
reproduction dependent on father
What is pathenogenesis
Reproduction dependent on the mother
What does retention of a polar body result in
Parthenogenesis 46XX
What happens if you get an empty egg fertilised by a sperm
Sperm doubles up, androgenesis 46XX
What is a hydatidiform mole a result of
Androgenetic –> complete moles usually due to homozygous 46XX.
Get proliferation of abnormal trophoblast issue
May get MALIGNANT trophoblastic tumour
What does parthenogenesis result in
Benign ovarian teratomas
Derived from oocyte after their first or second meiotic division
Diploid –> varying features, mostly epithelial tissues. Lacks skeletal muscle, placenta, membranes etc.
Why do parthenogenic embryos die
Failure of development of extra embryonic structures e.g. trophoblast
When do androgenic embryos dei
At the 6 somite stage, good extra-embryonic membranes developed but poor embryo development
What is genetic imprinting
Genes imprinted with a memory of the maternal/paternal origin –> ensures functional non-equivalence of the genes
How is genetic imprinting encoded
EPIGENETIC - not in the DNA
Due to modifications during gametogenesis
Affects the expression of 100-200 genes
What is Angelman Syndrome
Maternal deletion in chromosome 15
Causes ‘puppet children’ –> facially dysmorphic (smiling/laughing), mental handicap, seizures and ataxia/jerky movement
Main causes of Angolan Syndroe
Deletion in maternal chromosome 15 (75%)
Uniparental disomy (1%) - both paternal genes
Mutation (2-5%) –> in the UBE3A gene that is only expressed on the maternal genes –> inactivated in paternal genes
What is Prader-Willi Syndrome
Infantile hypotonia Hyperphagia --> causes obesity Hypogenitalism in males, cryptochidism Small hands/feet Mental handicap
Causes of Prader-WIlli syndrome
Deletion in paternal genes
Deletion in chromsome 15 (75%)
Uniparental disomy (25%)
UBE3A mutation in paternal gene has no effect as paternal version is inactivated anyway
Are DNA Methyltransferases reversible or irreversible
Usually reversible
Where does DNA methylation occur
At CG diculeotides - which are involved in gene regulation
Where do CpG islands usually occur
Unmethylated clusters usually in the promoters of genes allowing transcription to occur
What happens if there is methylation in CpG islands in gene promoter regions
Silences the transcription of the gene
Do imprinted genes show mono allelic expression
Yes
What do paternal genes drive
Drive foetal growth, high foetal fitness and high foetal mortality
What do maternal genes drive
Restrain foetal growth, high mortality, poor long term reproductive potential but better maternal survival rate and reproductive fitness
What is Beckwithh Wireman Syndrome
Where the paternal drive of genes wins
High birth weight, organomegaly, tumour risk, hypoglycaemia, sporadic, epigenetic abnormalities
FOETAL OVERGRWOTH
What is Russell - Silver Syndrome
Maternal drive wins –> growth retardation
Persistent post natal growth failure, triangular face, assymetry
What chromosome abnormalities cause BWS and RSS
Abnormalities in chromosome 11p15.5!
What drives fetal growth
IGF2 –> normally expressed on the paternal side
What are the impacts of hypomethylation on chromosome 11
Decreases IGF2 –> causes RSS
What are the impacts of hypermethylation on chromosome 11
Increases IGF2 –> causes BWS
When does imprint switching occur
Must remember during somatic development
Forget at gametogenesis
New parental imprint is established –> essential for normal growth and development
What chromosome is PGK1 on
X chromosome
Why does X inactivation occur
Ensures male and females have equivalent doses of genes on chromosomes
How does X-Inactivation occur
EPIGENETIC SILENCING
Why is X-inactivation different to imprinting
Whole X-chromosome is silenced
Random choice of chromosome silenced
Occurs early in embryogenesis in the blastocyst –> get patches of cells with different X-chromsomes inactivated
Why do you get tortoiseshell cats
Different X-inactivation in groups of cells
What is hypohydriotic ectodermal dysplasia
Female carrier of X-linked mutation
Due to X-inactivation get patches of skin with/without sweat glands
Test with starch/iodine
Are females epigenetic mosaics
Yes due to patches of cells with different X’s inactivated
Hence female carriers of X-linked mutations such as Haemophilis and Duchennes have some functional and some abnormal cells –> consequence is variable and unpredicatable
What is pharamcokinetics
What the body does to a drug
What is pharamcodynamics
what the drug does to the body
what is stratified medicine
selecting therapies for groups of individuals with shared biological characteristics
What is personalised medicine
therapies tailored to individuals
Are SNPs usually functionally significant?
NO - but if proline produced causes kinks in protein which is bad
What is the normal response rate to cancer drugs
Approx 20% due to genetic Varaition
What does Thiopurine Methytransferase do? (TPMT)
Inactivates certain drugs –> mutations in it mean azothiprine (immunosuppressant) and 6-metacarptopirone and 6-thioguanine (chemo) aren’t inactivated hence you get toxic products
Mutation means higher drug toxicity as not inactivated
Whos is TPMP 3A common in
White anglo saxons.
Who is TMPT 3C common in
African americans
What are n-acetyltransferases?
Liver enzymes that deactivate drugs by acetylation
Mutations mean you can get slow or fast acetylators!
What drugs do n-acetyltransferases inactivate
Isonizaid (for TB)
Sulfasalazine (for Crohns)
Hydralazine (hypertension
Who does fast acetylators arise in>
Nomadic populations with high meat eating diet
What is succinylcholine
Muscle relaxant used in anaesthesia (stops breathing)
Related to curare in poison darts
Mutation in what gene alters succinylcholine activity
Mutation in BCHE gene decreases bubrylcholinesterase activity
This enzyme normally deactivates succinylcholine
Hence mutation prolongs succinylchlines effects –> can lead to death if no ventilation
What does mitochondrial MT-RNR1 gene encode
Encodes mitochrondiral 12s RNA
What is amino glycoside induced hearing loss
G to A mutation, changes the mitochondrial rRNA structure to resemble E.Coli 165
Amino glycosides more likely to bind to this rRNA –> increases the risk of hearing loss at a younger age
Is amino glycoside hearing loss maternally or paternally inherited?
Maternally as it is on mitochondrial RNA
What mutations affect warfarin metabolism
VKORC1 and CYP2C9 mutations
What do 20% of breast cancer overexpress
HER-2 (Human epidermal growth factors receptor 2)
What can we treat HER-2 overexpression with
Trastozumav - a monoclonal antibody to HER-2
What mutation is seen in 50% of melanomas
BRAF mutation (BRAF is a serine protein kinase) Valine to glutamic acid mutation
What can we treat BRAF Mutation in melanoma with
Vemurafonib! But can have adverse effects in those without the mutation!
What is Huntingtons Diesease
A progressive neurogenerative disorder
Affects movement
Depresses mood
Loss of cogntiion, function, memory loss
When does huntingtons generally onset
35-44
How is HUntingons inherited
Autosomal dominant - complete penetrance
HTT Gene on chromosome 4 –> contains a series of CAG nucleotide repeats
What is Huntingtons caused by
An expansion of CAG nucleotide repeats on chromosome 4
How many CAG nucleotide repeats is needed to cause Huntingtons
Over 40 usually
What does CAG encode
Glutamic Acid
How does CAG nucleotide repeats cause the huntingtons disease
Abnormal proteins with increased glutamic acid
Form PolyQ cellular protein aggregates
Basal ganglia affected especially caudate nucleus
Are triplet repeat disorders associated with anticipation?
Yes –> they are unstable and prone to expand
Which diseases in anticipation are linked to gender?
Huntingtons - paternal Myotonic Dystrophy (AD) - maternal Fragile X (XL recessive) - maternal means more likely to expand if you inherit it from the mmother
What is the link between CAG nucleotide repeats and age of onset
Higher number of CAG nucleotide repeats causes lower age of onset
BUT applies to population as a whole but huge variation in individuals so can’t predict individually
Do we offer testing on under 18s for Huntingtons
No - only prenatal and if positive then must have an abortion
What is the treatment for Huntingtons
Symptomatic treatment only
No prevention or cure
Testing does NOT save lives but allows people to prepare
