Genetics part 3 Flashcards
What are 5 of the genes that cause DC?
- DKC1
- TERT
- TERC
- TINF2
- RTEL1
What is DKC1?
- Dyskeratosis congenita 1
- Encodes the protein called dyskerin
- Core component of telomerase
What is TERT?
The reverse transcriptase component of telomerase
Uses TERC as a template to synthesise telomeric DNA
What is TERC?
RNA component of telomerase
Act as a template for TERT
What is TINF2
A shelterin component
Protecting the telomere
What is RTEL1?
A regulator of telomere elongation
A DNA helicase that resolves D-loops during replication
What is pathophysiology of DC?
- Mutations in DC genes result in defective telomere maintenance
- Defective telomere maintenance results in premature senescence and apoptosis
- Early loss of cells (e.g. stem cells) leads to progressive development of disease features
- This is most pronounced in rapidly dividing tissues, notably the bone marrow
What are BMF syndromes?
Inherited
What is Dyskeratosis congenita?
Clinically and genetically heterogenous BMF syndrome
What are telomeres?
Specialised structures that protects the end of each chromosome
What are three distinct pathways that are defective in the inherited BMF syndromes?
- Fanconi anaemia
- Shwachman Diamond
- Dyskeratosis congenita
Fanconi anaemia
FANC genes
Involved in DNA damage response
Shwachman Diamond
Only 1 gene that causes this disease
Defect is present in the ribosome
Dyskeratosis congenita
Telomere maintenance
TERC, TERT
What is ERCC6L2?
New disease gene
Allelic series in exome sequencing data
What does ERCC6L2 stand for?
excision repair cross-complementation group 6 like 2 gene
Homozygous Arg655*
Red is loss of variant function
Green - missense
What is ERCC6?
DNA binding protein
Transcription coupled excision repair
What does mutation in the ERCC6 cause?
Cockayne syndrome
Not associated with bone marrow failure
What does ERCC6L2 play a role in?
DNA damage response
Mitomycin C
- Causes interstrand cross link
- Key test for people with Fanconi anemia
- Fanconi anaemia very sensitive to this drug
What does Irofulven cause?
Adducts
What is R-loops?
Occurs every time a gene is transcribed
RNA polymerase ploughs along the DNA making RNA and loop back on itself
R loop are dangerous and need to be re-solved
RNA coated with proteins – looked after as soon as it is made
2 loss of function variants in affected individuals
What is DNAJC21
- Disease causing genes
- Spectrum of phenotypes overlapping
- Homozygous - biallelic - both alleles are affected
What is Jjj1?
- Ribosome maturation
2. Involved in ribosome biogenesis
Ribosome biogenesis
- The rDNA locus in the genome – is the DNA that encodes for the ribosomal proteins
- It is repeated massively in vast tracks as we make a lot of ribosomes
- We transcribe the locus and process it and process it down again and get 2 subunits forming
- The large subunit will try to get out of the nucleolus to the cytoplasm
- To do that, it needs accessory proteins, there are a number of enormous accessory proteins involved in getting a ribosome made e.g. 200 proteins involved in ribosome assembly
- They get onto the ribosomes to get it out into the cytoplasm where it is joined to two other proteins which all stick together and cause reaction and kick the red protein back into the cytoplasm
How many ribosomal subunit cross the nuclear pore every minute?
20,000
What is theory of defective ribosome maturation?
Disturbs stem cell function
Also leukaemia promotion
What is SDS (shwackman diamond syndrome) characterised by?
- BMF
- pancreatic insufficiency
- Predisposition to leukaemia
What bis required for the last stage of 60S subunit maturation?
SBDS