Bioinformatics, gene to function to clinic, genomic imprinting Flashcards
What does LCA stand for?
Leber’s congenital amaurosis
Can only see very limited central vision
Gene therapy treatments for LCA and why?
Eye is immune privileged and accessible for subretinal injection.
RPE65 gene in dogs.
Pharmacogenetics definition
Correlation between the effect of drugs and the genetic constitution of patients
Cytochrome P450 oxidases
Multigene family of enzymes found in liver. Responsible for metabolic elimination of most drugs in use.
What CYP2D6?
highly polymorphic cytochrome 450 family member.
Metabolises 25% of drugs
People can be non-metabolisers or ultra-rapid metabolisers
Parthenogenesis definition
Asexual reproduction in which the offspring develops from unfertilised eggs
Androgenesis definition
Embryo fails to develop but the trophoblastic tissues develop normally
Hydatidiform mole definition
Hydatidiform mole is a rare mass or growth that forms inside the womb (uterus) at the beginning of a pregnancy. It is a type of gestational trophoblastic disease
Androgenetic hydatidiform mole
Complete moles which most are homozygous (46, XX)
Proliferation of abnormal trophoblast tissue
Parthenogensis what is it?
Benign ovarian teratomas
Derived from oocytes which have completed first or both meiotic divisions.
They’re diploid and produce wide spectrum of tissues but mainly epithelia
Uniparental conceptions in the mouse how successful are they?
Parthenogenetic embryos die due to failure of extraembryonic structures (trophoblast, yolk sac)
Androgenetic embryos die at 6 somite stage so has well developed extra-embryonic structures but poor embryo development
Why do uniparental conceptions fail? They have normal karyotype and normalgene dosage.
Different roles of maternal vs paternal genes.
Concept of genomic imprinting: mothers and fathers somehow imprint their genes with a memory of their materal or paternal origin.
Genomic imprinting definition
A mechanism that ensures the functional non-equivalence of the maternal and paternal genomes
Features of genomic imprinting
Not encoded in the DNA nucleotide sequences i.e. epigenetic
Determined via modifications to the genome in gametagensis (spermatogenesis vs oogenesis)
Angelman syndrome
Facial dysmorphism Mental handicap Seizure disorder Ataxic, jerky movements Aka puppy disorder
Prader-Willi syndrome
Infantile hypotonia Mental handicap Male hypogenitalism/ cryptorchidism Small hands and feet Hyperphagia - obesity Stereotypic behaviour
Cytogenetic abnormalities for Angelman and Prader-Willi syndrome
Deletion of chromosome 15
Found in both syndromes
Always de novo risks so recurrence risks very low
Syndrome dependent on if its on male or female side.
Dependent on methylation
Features of DNA methylation
Post-synthetic DNA modification
Epigenetic so does not normally alter DNA sequence
DNA methyltransferases
Reversible
Has to be maintained following replication
Occurs at CG dinucleotides, many promoter regions are spared making CG islands
What is Beckwith-Widemann Syndrome?
Foetal overgrowth - high birthweight (>5kg) Organomegaly Hypoglycaemia Asymmetry Tumour risk Sporadic occurrence Epigenetic abnormalities
Russell-Silver syndrome
Growth retardation
Triangular face (preserves more brain size)
Asymmetry
Sporadic occurrence
Hypomethylation of 11p15.5 for IGF2 (insulin-like growth factor 2)
Less IGF2 production
Russell-Silver Syndrome
Hypermethylation of 11p15.5 for IGF2
More IGF2 leads to Beckwith-Widemann syndrome
Imprint switching features
Forgotten before gametogenesis
Establishes new parental imprint during gametogenesis
Features of a female carrier of an XL mutation
Hypohidrotic ectodermal dysplasia
Starch/iodine test
Patches of skin with or without sweat glands
When does X inactivation occur?
At a time when there are a small number of precursor cells.
Random skewing is possible
For carriers of XL mutations this affects clinical expression
It is unpredictable
Consequences of X inactivation
Females are epigenetic mosaics
Composed of patches of cells working on or other X chromosome
Carriers of XL mutations have some functionally defective and some normal cells
The consequence of this functional mosaicism may be unpredictable and may also be disease specific
