Genetic disorders Flashcards
What are transition mutations?
Purine -> purine
Pyrimadine -> pyrimadine
Purines = AG Pyrimidines = CT
What are transversion mutations?
Purine -> pyrimidine
Pyrimidine -> purine
What are nonsense mutations?
What are missense mutations?
- STOP codon placed in DNA sequence
- Different Amino acid encoded for and inserted into DNA sequence
How do mutations alter to polymorphisms?
Polymorphisms are when there are multiple alleles for a gene within the population, may not alter activity of the protein but causes differences in amino acids between individuals
Give an example of how huntigtins is a polymorphism
Within the huntigtin gene between 4-36 CAG repeats is normal
This CAG nucleotide encodes for a polyglutamine stretch in the huntingtin protein
> 40 CAG repeats leads to the disease huntigtins
What are inherited mutations?
Those that occur within germ cells and the cells of one/both parents. These are passed onto the offspring
What are sporadic/de novo mutations?
Mutations that occur outside of the germ line
Neither parent has the mutation in their somatic cells
Describe direct repair
Alkyltransferases remove O6 akylguanine and O4 akyl thiamine from the DNA sequence
These contribute to cancer, incorrect base pairing and also strand breakage
What are the 2 main spontaneous reactions leading to DNA damage?
Depurination
Deamination: Cytosine -> Thymine transition or Cytosine -> uracil transition ( causes wrong base to be inserted)
Describe base excision repair and what it does
BER removes single incorrect/damaged bases
- Initiated by DNA glycolysases which excise the damaged DNA base
- This leaves apurinic or apyridinic sites
- Endoucleases can bind to the AP sites + cut the DNA
- Exonucleases remove the ribose phosphate backbone of the DNA
- DNA polymerase refills gap which is sealed by DNA ligase
Describe nucleotide excision repair and what it does
Nucleotide excision repair removes sequences of DNA damage up to 30 bases long
May be caused by oxygen radicals, radiation or chemicals
XP-C + 23B proteins recognise the initial DNA damage
This complex recruit transcription factor 1 human complex which contains helicase subunits to unwind the DNA
XP-G + RPA proteins bind to the complex to unwind the helix and form a sequence of 25 bases
Endonucleases cut the damaged DNA on either side removing the damaged DNA as well
Damaged DNA sequence is degraded
DNA polymerase + ligase refill the gap
What happens if the incorrect base is added?
3’ growing end of the strand moves to exonuclease site
Incorrect base is removed
3’ growing end flips back to the polymerase site to continue elongation
Describe mismatch repair and what it does
Corrects DNA damage which occurs during replication
MHS2 + MHS6 proteins bind to the mismatched DNA segment. This distinguishes between the template strand and DNA damage
MHL1 + PSM2 are recruited
Endonuclease cuts daughter strand
Helicase unwinds DNA
Exonuclease removes DNA from cut end of double strand as well as the mismatched base
DNA polymerase and Ligase fill the gap
What does homolgous end rejoining use?
What does it repair?
Information which is still intact on the opposite sister chromatid/chromosome or on the same chromosome
Repairs double stranded DNA breaks
What do the BRCA1/2 genes encode for and what do mutations in these genes predispose to?
Proteins involved in double stranded DNA repair
Predispose to ovarian and breast cancer
Describe homologous end rejoining
- Exonucleases removes a DNA strand from each side of the break
- These single stranded DNA strands invade the sister chromatid
- DNA polymerase uses the sister chromatid as a template + there is complementary base pairing of single stranded DNA to elongate in the 5’ to 3’ direction
- Single stranded DNA strands are released from the sister chromatid and pair with one another
- DNA polymerase and ligase fill the gap
Describe non homologous end re joining
Repairs double stranded DNA breaks when there is no opposite chromosome or sister chromatid intact
Single strands are removed from each end
These single strand overhangs are joined together
The strands are filled and ligated to rebuild the double helix but are missing bases present in the original double helix
Describe autosomal dominance and give an example of an autosomal dominant condition
Only 1 allele present produces the phenotype, one mutant allele masks the function of another
Achondroplasia ( type of dwarfism)
- Mutation in the FGFR3 gene
- Produces a mutant receptor which is activated in the absence of FGF. Ligand independent activation
- Receptor activation limits the expansion of growth plates in long bones
Describe autosomal recessive and given an example of an autosomal recessive conditions
2 mutant alleles must be present on each autosome to be expressed in the phenotype
Carriers have one normal allele and one mutant allele. no phenotype expressed
Example = Hurler Syndrome
- Lysosomal disease caused by a deficient/absent IDUA enzyme
- This enzyme is involved in degradation of glycosaminoglycans
- Developmental delays, skeletal, cardiac and respiratory abnormalities
What is X linked recessive ?
Give an example of 2 X linked recessive conditions?
Mutant allele on X chromosome, only shown in females if two copies of mutant allele on each X chromosome are present
More common in males, mutant allele on X chromosome will show in the phenotype
DMD : Mutant dystrophin protein which links cytoskeleton to ECM
Hunter Syndrome
- Caused by a deficient/absent IDS enzyme
- Causes accumulation of heparin sulfate and dermatan sulfate, glycosaminoglycans
- Clinically linked with Hurler Syndrome
What is X linked dominant and give an example of an X linked dominant condition?
Mutant allele on X chromosome
Fragile X syndrome: Caused by CCG repeats on FMR1 gene
> 200 CCG repeats causes hypermethylation of Cpg nucleotides + silencing of the FMR1 gene
What is Y linked dominant and give an example of Y linked dominant conditions?
Only present in XY males caused by a mutant allele on Y chromosome
Example = X chromosome infertility due to whole gene deletion in AZF region of Y chromosome
This area is responsible for sperm production
Describe mitochondrial inheritance
Maternal inheritence - only the eggs contribute to mitochondria development
Example = Leber hereditary optic neuropathy
- Caused by mutations in any of the 4 genes (mitochondrial DNA) encoding for NADH hydrogenase subunits
- Causes degeneration of retinal ganglion cells and hence vision loss
What is genomic impriting?
Only the non imprinted allele is expressed, which allele is imprinted and effectively silenced is dependent on the sex of the parent
- E.g mouse receives a mutant recessive allele and a normal dominant allele
- Mutant recessive allele is expressed due to silencing of dominant allele by genomic imprinting
Describe prader Willi syndrome
Deletion in Paternal gene - SNRP2
Paternal gene expressed
Maternal gene silenced
Only non imprinted allele is expressed
Hyperphagia, obese, hypogonadism
Describe Angelman syndrome
Deletion in maternal gene - UBE3A
Maternal gene expressed
Paternal gene silenced
Uncontrollable laughter
What is the function of SNRP2?
mRNA splicing
What is the function of UBE3A?
ubiquitin pathway
What is Kallman syndrome?
Genetic disorder in which puberty is not fully complete or doesn’t start
- Caused by lack of release of GnRh or no activation of this hormone
- Causes lack of tesosterone/oestrogen
- CHH - Congenital Hypogonadotrophic hypogonadism
- Normal CHH symptoms
- If untreated leads to poorly defined sexual characteristics, hypogonadism, infertility, osteoporosis
- During 1st 10 weeks of development the GnRH releasing neurones migrate from the nasal placode to the hypothalamus. Defects in olfactory nerve fibres prevent this migration.
What is aneuploidy?
Give examples of some of these disorders
Extra/missing chromosome
Down’s Syndrome : Trisomy 21
Turner’s Syndrome: Absence of X chromosome
Give some examples of chromsomal structural abnormalities
Cat cry Syndrome: Deletion of chromosome 5p
High pitched cry, low muscle tone, low birth weight, small head
Pallister Killan Syndrome: Extra chromosome 12. Moacism with some cells normal and some with extra chromosome 12.
