Genetic Diseases Flashcards
What is a copy number variant mutation?
When a given genetic sequence of variable length (from few nucleotides to whole chromosomes) is present and repeated a variable number of times
Change in number of repeats may be considered a mutations e.g Huntingtons disease
What are microsatellites in genomics?
A type of copy number variations - small repetitive sequences that vary in length between individuals
Typically underly DNA fingerprinting.
What is the most common type of mutation causing disease?
Single nucleotide variants
What is the CFRT protein?
Is an anion channel that transports Cl- and HCO3-
Is an ATP-binding cassette transporter, regulated by PKA (phosphorylation)
Associated with mucus production - typically lung epithelium and pancreas
What is the functional affect of a mutated CFTR in CF?
Adherent mucus plug in submucosal glands - dehydrated and thick
Destroys periciliary layers - decrease mucociliary transport
Recurrent infections
Bronchiectasis.
What are the six different classes of mutation present in CF?
1 - protein synthesis (typically premature stop codons = abnormal protein)
2 - trafficking = does not reach membrane
3 - channel gating/opening = cannot by regulated
4 - channel conductance = reduced Cl- passage when open
5 - alternative splicing (reduced protein numbers)
6 - recycling and halflife
What are the functional consequences of the CFRT mutation in CF?
Loss of mucociliary transport leads to chronic infections = chronic inflammation
What are some CFTR related disorders?
Chronic sinusisitis
Nasal Polyps
Primary Sclerosing Cholangitis
Cervical mucus abnormality
CBAVD
Recurrent pancreatitis
Bronchiectasis
What are some multifactorial complications of cystic fibrosis?
Antimicrobial allergy and polypharmacy
increased arterial stiffness
GI malignancy
Dyspepsia
Female urinary incontinence
Infection MDR microorganisms
Renal failure
MSK abnormalities
Hearing and vestibular impairement
What is the most common mutation in CF?
F508del found in 70% of patients
This is a type 2 mutation (trafficking)
What experimental causative treatments are being investigated for CF?
This can be targeting…..
Translational
On channel modulators
Intracellular trafficking
CFTR modulators
Geneotherapy - CRISPR in preclinical trials
What ‘potentiator drugs’ exist to treat CF on NHS?
Potentiators - help the CFTR channel open to increase Cl- outflow - ivakaftor
What corrector drugs exist to help treat CF on the NHS?
Correctors - aid the protein folding so more CFTR make it to the surface (Tezakaftor and Elaxakaftor both contain ETI ‘Kaftrio’)
What is n example of discrimination in medicine regarding cystic fibrosis?
Origin?
‘White people disease’ - black man late and poor diagnosis at age 54yrs.
F508del originated in ‘Beaker people’ of southwestern Europe, tend to be white.
High rate of heterozygosity has been maintained.
How does global genetic variation relate to genetic disease?
Africa - widest genetic variation
Other regions - less variation as bottle neck during original migration out of Africa
Rest of regions high risk of recessive conditions
Require more research in African ethnicity as contain widest variety of genes.
What is meant by transcriptomics?
The study of transcripts - all RNA molecules
What is the cellular origin for colorectal cancer?
Instestinal crypts - LGR5 positive stem cells are cancerous
Found at base of crypts - sensitive to multiple developmental signalling pathways including RTK, BMP, Notch and Wnt - cause proliferation.
What are the two pathways of origin for colorectal cancer?
- Originate from adenoma - such as in Lynch syndrome -> mutation in RAS or Wnt signalling or chromosome instability (microsatellite instability)
- Originate from serrated polyps -> Wnt and Ras and Braf, PI3K, TGFB
Both due to oncogenic transformation of stem cells.
How are transcriptomes important to classifying colorectal cancer?
Can be identified -> allows classification on gene expression/molecular profile.
Results in four subtypes of colorectal cancer -> Consensus molecular subtypes 1/2/3/4 each with a unique gene expression signature.
What consensus molecular subtype is most worrying? Why?
Type 4
Highest over expression of mesenchymal signatures - demonstrates the epithelial to mesenchymal transition -> most cancerous potential
Correlates with lowest overall survival and relapse free survival
What is spatial genomics?
Considers transcriptomes, epigenetics (chromattin) and singular genes -> identifies expression, concentration of expression and relative location e.g comparing one tissue type to another between and within organisms or different places within a single tumour
What was the key learning relating to cancer from spatial genomics?
Hox genes found to have a role in tumorigenesis.
Increase intratrumour variation = poor prognosis
Lower immunological constant of rejection = lower immune expression = poor survival.
How does the genetic subtype of cancer relate to the phenotype of cancer seen?
CMS3 - benign adenomas and low grade dysplasia
CNS2 - high grade dysplasia and carcinoma
CNS4 - only carcinoma
How does time relate to the genetics fingerprint of colorectal cancer?
Majority of patients remained with same CMS for precursor and carcinoma
However some migration between groups - particularly the inc in CMS4 - demonstrate ability of tumours to evolve.
