GiM week 8-10 Flashcards
what is another name for diGeorge syndrome?
and what chromosome is the microdeletion on?
velocardiofacial syndrome
(actually not identical but almost the same)
chromosome 22 (specifically: 22q11.2)
what is a pathological variant?
a genetic variant from the ‘wild type’ that CAUSES a disease in the phenotype
what is COMT and what is the association with alcoholism?
Catechol-O-methyltransferase
an enzyme, if you have a certain variant form of this enzyme (caused by genetic variation) then it increases the likelihood, if you are a social drinker, of becoming an alcoholic
what two types of mutations will microarray analysis NOT detect?
- balanced translocations
- mosaicism (depends)
this is because microarrays measure gene dosage, which doesn’t change with balanced translocations and doesn’t change universally with mosaicism
what does FISH stand for?
fluorescence in situ hybridisation
what are the functions of T-Box genes?
encode transcription factors involved in the regulation of developmental processes
what is blepharophimosis?
narrowing of the eye opening
what is sclerocornea?
clouding of the cornea to a varying degree
what are the 5 major medicalproblems associated with DiGeorge?
- heart defects
- poor immune system control
- cleft palate
- complications related tolow blood calcium
- delayed development (w. behavioral + emotional problems)
what % of breast cancers are caused my inherited mutations of brca1 + brca2 genes?
5-10%
what is retinitis pigmentosa?
a collection of genetic mutations which causes inherited late-onset blindness (via retinal degeneration)
- loose peripheral vision and night vision first, so get tunnel vision, then go completely blind
what does fully penetrant mean?
if you have the mutated gene then you definitely WILL have/get the condition! - eg huntingtons
describe treacher-collins syndrome
craniofacial deformities
- including eyes (downward slanting), ears and cheekbones
- normal intelligence
what are the two main invasive methods of prenatal testing used? and at what gestation are they used?
chorionic villus sampling
- about 11 weeks
- more common
amniocentesis
- about 17 weeks
what is preimplantation non-disclosure testing? for huntingtons
eg Want to make sure embryo does not have mutation even if don’t know mothers risk, so test genes and make sure no genes from grandmother (who is infected)
what is the difference in obesity trends in monozygotic and dizygotic twins?
Twins separated at birth
Dizygotic twins have variety in BMI
Monozygotic twins have very similar bmi
what is leptin?
what hormone opposes its actions?
the ‘satiety hormone’
made by adipose cells, inhibits hunger
opposed by ghrelin (the ‘hunger hormone’)
what happens in leptin deficiency?
the mouse/person lacks the ‘ob’ gene, which codes for leptin
so you never feel full –> get very fat
nb you can also have mice/people who lack a gene which codes for the leptin receptor, so the adipose cells are producing leptin but the brain is not receiving that signal
what is Leber’s congenital amaurosis (LCA)?
- Rare inherited eye disorder (autosomal recessive)
- blindness at birth/early infancy
- over 22 genes implicated
what are the 2 reasons that the eye is a good place to use gene therapy?
- immune privileged
- easily accessible, via subretinal injection
what gene is targeted for gene therapy of LCA?
RPE65
what is pharmacogenetics?
correlation between the effects of drugs and the genetic constitution of patients
what are cytochrome P450 oxidases?
give an example of one?
Multigene family of enzymes found predominantly in the liver
Responsible for the metabolic elimination of most drugs currently used
Also important for converting pro-drugs to their active forms (eg codeine)
example: CYP2D6
what effect does CYP2D6 have on tamoxifen metabolism?
CYP2D6 converts tamoxifen to its active metabolite: endoxifen
people with reduced CYP2D6 function are thus poor metabolisers of tamoxifen –> worse survival (when being treated w. tamoxifen for breast cancer)
what does androgenesis mean?
male reproduces without female partner
“ANDROgens are typically MALE sex hormones, such as testosterone”
what does parthenogenesis mean?
female reproduces without male partner
in normal, sexual, fertilisation when does the sperm fertilise the egg?
at the same time as the second meiotic division (expulsion of 2nd polar body)
what causes a hydatidiform mole (aka molar pregnancy)? and what is it?
androgenetic conception
(no female genetic tissue, 2 sets of male genetic tissue)
proliferation of abnormal trophoblast tissue (no remaining embryo)
produces a positive preganancy test
what causes benign ovarian teratomas and what are they?
parthenogenesis
(lots of eggs, no sperm)
wide spectrum of tissues,predominately epithelial (fat, hair, teeth) - no skeletal muscle
no membranes/placenta
why do parthenogenetic embryos die?
due to failure of development extraembryonic structures:
- yolk sac
- trophoblast
why do androgenetic embryos die?
poor embryo development
nb well-developed extra-embryonic membranes
what is genomic imprinting?
mothers and fathers somehow ‘imprint’ their genes with a memory of their paternal or maternal origin
nb this is ‘forgotten’ in gametogenesis (ie not passed on to grandchildren)
it is NOT ENCODED in the DNA nucleotide sequence, and so is EPIGENETIC
“epi = on top of”
what genes are affected by imprinting?
Affects the expression of a small subset of 100-200 genes (ie not all genes affected by imprinting)
describe angelman syndrome (4)
facial dysmorphism
- –wide mouth, drooling
- –smiling/laughing appearance
mental handicap
- –microcephaly
- –absent speech (mute)
seizure disorder
ataxic, jerky movements
- used to be referred to as ‘happy puppets’
“ANGELs are always happy –> ‘happy puppets’ syndrome”
describe prader-willi syndrome (5)
infantile hypotonia
- feeding problems
- gross motor delay
mental handicap
male hypogenitalism/cryptorchidism
small hands and feet
hyperphagia
- obesity
“PRADA want people skinny, but these people are fat”
what is the cause of both angelmans and prader-willi syndromes?
why do they have different phenotypes?
small deletion on chromosome 15
(practically always de novo)
because of imprinting:
Angelman – loose a bit of mum’s C15
Prader-willi – loose a bit of dad’s C15 (“dad’s have willys”)
What is the other cause of angerlmans/prader willi?
uniparental disomy
- both copies of chromosome 15 have come from one parent
prader-willi = 2 copies from mum
angelmans = 2 copies from dad
why does monoallelic expression occur?
due to dna methylation at CG nucleotides (after replication)
needs to be ‘put back on’/methylated again every time a cell divides
what is DNA methylation?
Post-synthetic DNA modification
Epigenetic
(Does not normally alter DNA sequence)
carried out by DNA methyltransferases
Reversible
Has to be “maintained” after replication
Occurs at CG dinucleotides
what are CG ‘islands’
most genes are methylated (at CG dinucleotides)
But CG dinucleotides in many promoter regions (/genes) are spared (so are unmethylated) =
CG “islands”
if these are methylated then gene is ‘silenced’ and cannot be transcribed
why do imprinted genes show monoallelic expression? (and what does this mean?)
monoallelic expression means one allele (version of the gene) is ‘silenced’
in imprinting, there are epigenetic differences between maternal and paternal alleles (ie one is methylated and one is not, causing the methylated one to be silenced)
nb methylation is not all there is to it, there are other epigenetic differences (eg in histones) which also control gene expression
what is the hypothesis as to why imprinting has evolved evolutionarily?
Evolutionary interests of mum and dad are somewhat different
Unrestrained foetal growth may lead to difficult delivery which can lead to long term problems in mother, so mother may not be able to reproduce again
Whereas dad doesn’t care about mothers future fertility (if polygamous), they want baby to be big as possible – as high birth weight means lower mortality
so, overall (super-generalising), dad’s genes lead to more growth and mum’s genes lead to less growth
(nb however this goes against angelmans/prader-willi phenotypes as prader-willi are normally fat, but they have LACK of paternal chromosome)
describe beckwith-wiedemann syndrome (5)
foetal overgrowth
- high birthweight
organomegaly (large organs)
hypoglycaemia
asymmetry
high risk of childhood cancer
“beckwith-WIEDERMANn makes you a WIDER MAN, ie it’s an overgrowth condition”
describe Russell-silver syndrome (3)
growth retardation
- low birth weight
- persistent postnatal growth failure
triangular face
- brain is more normal sized, just rest of body that is smaller
asymmetry
“jack RUSSELL terriors are SMALL, as is SILVER jewelry”
what is the cause of beckwith-wiederman syndrome?
epigenetic changes on chromosome 11
HYPERmethylation
- -> H19 on maternal chromosome SILENCED
- -> IGF2 on paternal chromosome works as normal (as methylation after the IGF2 gene switches it on)
–> overgrowth
nb IGF2 (insulin-like growth factor) is a major foetal growth promoter
what is the cause of Russell-silver syndrome?
epigenetic changes on chromosome 11
HYPOmethylation
- -> H19 on maternal chromosome works as normal
- -> IGF2 on paternal chromosome is silenced (as methylation after the IGF2 gene switches it on)
–> stunted growth
nb H19 gene has a rolein the negative regulation of body weight
what is imprint ‘switching’?
Imprinting must be “remembered” during somatic development
“Forgotten” before gametogenesis
Erasure of grandparental imprint
Establishment of new parental imprint
- During gametogenesis
- (Oogenesis for most genes)
what are pseudoautosomal regions of DNA?
a little bit of dna which is the same on X and Y chromosomes
how do females deal with having double dosage of all X genes?
(ie dosage compensation)
by using monoallelic expression
- achieved by epigenetic silencing of one whole copy of X chromosome (= X-INACTIVATION)
nb somatic cell ‘remember’ silenced status, reversed in germ cells
what is X-inactivation also called
Lyonisation
“LIONS are CROSS animals, an X is a cross”
what are the 3 differences between X-inactivation and imprinting?
imprinting
- single genes are silenced
- same ones are in every cell in the body
- depends on whether paternal or maternal copy
X-inactivation
- whole X-chromosome is silenced
- different cell populations have different copy silenced (as silencing occurs at blastocyst stage, but after initial silencing, all daughter cells will be same as parent cells, ie somatic cell clones ‘remember’)
- random choice of parental chromosome, no relevance if came from mum or dad
describe the process of how X-inactivation occurs?
Both X chromosomes are initially active but then, early in development – blastocyst stage, each cell randomly decides which one to inactivate
But then daughter cells of all blastocyst cells inactivate same one as their parent one did (they ‘remember’)
This process occurs at random but is then clonal
describe a, physically visible, example of X-inactivation causing a mixture of cell populations
Tortoiseshell cats are ALL FEMALE, if they are heteroxygous for the colour gene (which is on the X chromosome) then, due to X-inactivation, they have diferrent cell populations and distribution of colour
what is hypohidrotic ectodermal dysplasia?
how does it manifest differently in men and women?
it’s an rare recessive X-linked mutation
In affected boys – sweat glands don’t develop
In female carrier – patches that have sweat glands and patches which don’t have sweat glands (due to random X-inactivation)
Can be visualised using starch and iodine on patient
what does X-activation mean for female carriers of X-linked conditions?
it means they have wildly varying phenotypes, depending on what random proportion of the cells have silenced mutated X-chromosomes and what tissue types these are found in (called functional mosaicism)
eg if carrier of duchenne muscular dystrophy has mutated Xs SILENCED in muscle tissue then normal phenotype, but a lot worse if mutated X’s are only NOT-silenced in muscles
what’s the difference between pharmacokinetics and pharmacodynamics?
pharmacokinetics: what the body does to the drug (absorption, metabolism, distribution + excretion)
pharmacodynamics: what the drug does to the body
(how it works, side effects etc)
what is stratified medicine?
selecting therapies for groups of patients with shared biological characteristics
Stratified medicine is based on identifying subgroups of patients with distinct mechanisms of disease, or particular responses to treatments. This allows us to identify and develop treatments that are effective for particular groups of patients. Ultimately stratified medicine will ensure that the right patient gets the right treatment at the right time
what is pharmacogenetics?
the study of inherited genetic differences in drug metabolic pathways which can affect an individuals response to a drug
these differences may result in a positive response to a drug therapy or an adverse drug reaction
(plays an important role in being able to offer stratified medicine to improve patient care)
what are 6 genetic variations which can affect drug metabolism?
- single nucleotide polymorphism (SNPs)
- deletions/insertions (whole gene or within a gene)
- translocations
- promoter polymorphisms
- gene amplification
all these things cause a change in the protein
what’s the difference between a missense mutation and a nonsense mutation?
missense: causes one aa to be substituted for another
(whole protein transcribed, with just one change in sequence)
nonsense: causes one aa to be substitued for a STOP codon
(transcribed protein is truncated)
what % of hospital admissions are due to an adverse drug reaction (ADR)?
6.5%
What is Thiopurine methyltransferase (TPMT) and why is it clinically relevant?
TPMT is an enzyme which metabolises thiopurine drugs (immunosuppresants, chemotherapy) from their inactive form to their active form
it is coded for by the TPMT gene, if there is a polymorphism in this gene it can reduce TPMT protein activity
If a patient taking thiopurines has this polymorphism then there is a greater chance of build up of the inactive drug –> damage to the bone marrow –> lots of problems
(nb patients with the ‘normal’ variant can also get these side effects but they are MUCH less common)
what is the drug Ivacaftor used to treat? and it which patients is it effective?
cystic fibrosis
- drug works by opening up CFTR channel slightly –> significantly improved symptoms
works well with CF patients with G551D genotype
no effect on homozygous f508del patients (but these make up 75 of CF patients)
What is the drug Succinylcholine used for? and what genetic variation causes it to have an increased effect?
muscle relactant used in anaesthesia (to stop breathing)
in normal patients: wears off after a few minutes
enzyme butyrylcholinesterase normal breaks it down in body
rare BCHE gene variant homozygote patients have reduced butyrylcholinesterase activity
- -> effects may last for an hour or more (+ risk of death if artificial ventilation is not continued)
- so knowing this info before they go into theatre would be very useful
What are aminoglycoside drugs used for? and which patients should they not be used in? why?
antiobiotics (against gram-negative)
Aminoglycosides are contraindicated in patients with mitochondrial diseases as they may result in impaired mtDNA translation, which can lead to irreversible hearing loss (earlier than they would have got it), tinnitus, cardiac toxicity, and renal toxicity.
However, hearing loss and tinnitus have also been observed in some patients without mitochondrial diseases, though at MUCH lower levels
what 2 genes affect people’s response to warfarin?
CYP2C9 (one of cytochrome p450 family)
vitamin K oxidoreductase complex 1 (VKORC1)
what is malignant hyperthermia and when does it occur?
an adverse drug reaction to many drugs used in general anaesthesia
it occurs in people with a certain autosomal dominant genetic variation
the adr involves a drastic rise in oxidative phosphorylation in all body cells –> hypoxia, hypercapnia, hyperthermia, eventually–> circulatory collapse and death if not treated
what is the brand name of Herceptin?
trastuzumab
what is Herceptin used to treat?
Herceptin is a monoclonal antibody to the HER2 receptor
20% of breast cancers have over expression of HER2
so Herceptin is successfully used with this 20% of patients
what are BRAF inhibitors? (give an example) and what are they used to treat?
50% of melanomas have a somatic mutation in the BRAF gene
so BRAF inhibitors target this mutation to slow/stop cancer growth
(but only work if you have this mutation)
an example: Vemurafenib
what are the three main sets of symptoms in Huntington’s disease?
Movements
Memory
Mood
“the three Ms”
what movement disorders are seen in Huntingtons? 5
chorea = involuntary movements
dystonia = twitching (caused by uncontrolled muscle contractions)
bradykinesia = slowness of movement
swallowing/choking difficulties
dysarthria = slurred/slow speech
what moods are seen in Huntingtons? 6
depression euphoria apathy anxiety aggression psychotic symptoms
what changes in cognition are seen in Huntingtons? 3
loss of executive functioning
rigidity of thought
memory loss/dementia
what is the mean age of onset of Huntingtons? and what is the median survival time after onset of symptoms?
35-44 (age of onset)
15-18 years survival after onset
what genetic abnormalities cause Huntingtons?
in normal people: 6-35 CAG trinucleotide repeats in the HTT gene (which codes for huntingtin protein)
in huntingtons: >40 CAG repeats in HTT gene
what part of brain is most affected in Huntingtons?
basal ganglia (esp. caudate nucleus)
what is anticipation?
the onset of a disorder occurs at an earlier age as it is passed from one generation to the next. Often this is associated with an increase in severity of symptoms
why is anticipation often associated with triplet repeat disorders?
Triplet repeat expansions are unstable and may increase (occasionally contract) when passed to the next generation
and when repeat gets longer–> earlier age of onset (+more severe symptoms)
what are the three most common triplet disorders?
Huntington disease (autosomal dominant)
Myotonic dystrophy (autosomal dominant)
Fragile X syndrome
(X-Linked recessive)
Is the risk of anticipation of HD higher if you inherit it from your mum or your dad?
your dad
So if your father has HD then higher chance that you will get more repeats than if it came from your mother!
- We don’t know why there is this gender difference
Is the risk of anticipation of myotonic dystrophy higher if you inherit it from your mum or your dad?
your mum
So if your mum has myotonic dystrophy then higher chance that you will get more repeats than if it came from your dad!
Is the risk of anticipation of fragile X syndrome higher if you inherit it from your mum or your dad?
your mum
So if your mum has fragile X syndrome then higher chance that you will get more repeats than if it came from your dad!
what is myotonic dystrophy?
adult-onset condition that affects muscle function
- worsening muscle loss and weakness
- cataracts
- heart conduction problems (eg heart block)
what is fragile X syndrome?
X-linked genetic condition
- developmental problems (incl. learning disabilities + sometimes autism)
- anxiety or attention deficit disorder
- can get seizures
- long, narrow face,
- large ears
- prominent jaw + forehead
- in males, enlarged testicles
what is haemochromatosis?
autosomal recessive condition
body absorbs too much iron
usually presents in middle age
treatment is regular phlebotomy (withdrawing of blood)
