Disease Mechanisms Flashcards
How does each mutation lead to phenotype:
Loss of function?
Gain of function
Dominant negative
- abolished or reduced protein function
- abnormal protein activity
- mutant product interfere with normal product function in heterozygous
What are the four types of loss of function mutation?
Qualitative
Quantitative
Regulatory
Large deletions
Give examples for qualitative and quantatative loss of protein product
Quantitative
- thalassemia
- autosomal recessive
- reduced rate of synthesis of globin chains to make haemoglobin
Qualitative
- sickle cell
- abnormal globin
- affects red blood cell shape and flexibility
Give an example regulatory loss of function mutation
Haemophilia B
- X linked recessive
- mutation in factor IX gene
- if in binding sites for transcription factors LF-A1/HNF4 and C/EBP will cause Haemophilia B Leyden
- if in Amdrogen response element will cause haemophilia B Brandenburg
Give two conditions associated with large deletion loss of function mutations
Duchenne muscular dystrophy and Becker muscular dystrophy
Both mutation in dystrophin gene causing frame shift
Both X linked recessive
DMD affects boys
BMD affected men
DMD more severe
What is the role of dystrophin?
Anchors contractile machinery to the sarcolemma
What are the types of dystrophin gene deletions?
99.3% intron
so most deletion break points are in introns and delete one or more complete exons
In DMD
- frame shift that causes loss of dystrophin
- e.g. delete exon 2 or 3 =DMD
In BMD
- still in frame but smaller partially functional protein
- delete exons 2&3 = BMD
Give an example gain of function mutation
T cell acute lymphoblastic leukaemia NOTCH1 mutations ion >50% patients Activating mutations Two hot spots 1) heterodimerization domain: ligand independent activation of NOTCH1 2) PEST domain: sustain NOTCH1 activity
Give an example dominant negative mutation
Osteogenesis Imperfecta type 3
- mutations in COL1A1 or COL1A2
- affects collagen
- mutation with most effect on protein synthesis not worst
- dominant negative mutant protein has dominant effect on triple helix assembly
What are dynamic mutations?
Those cause by expansion of existing polymorphic DNA Repeat sequence beyond a copy number threshold. Usually trinucleotide. E.g. HD and FraX
What are the features of polyglutamine diseases?
Progressive neuromuscular or neurodegenerative diseases
Modest expansions of CAG
In coding sequence
Dominant
Likely pathogenic mechanism is protein aggregation
Gain of function
What causes of the pathogenicity of PolyQ aggregates?
Sequestering important proteins Blocking cell vehicle trafficking Inhibiting proper proteasome function Affect mitochondrial function Toxic titration of chaperones away from rest of cells Cell apoptosis
What type of expansion is seen in FraX?
What is the mechanism?
Poly CGG
60-230 repeats is premutation
>230 is full mutation
FMR1 gene encodes FMRP1 protein
- RNA binding protein - shuttles between nucleus and cytoplasm, implicated in translation
- full expansion triggers mayhylation of DNA through Histone deacetylation which off the gene
- loss of gene function
What causes FraX associated tremor/ataxia syndrome?
Adult onset 55-200 CGG repeat in 5'UTR of FMR1 gene RNA gain of function -an elevation in mRNA level - mRNA inclusions - sequesters proteins
What is anticipation?
Phenomenon whereby symptoms of a genetic disorder become apparent at an earlier age and severer as it is passed onto the next generation. Dynamic mutations where size of expansion correlated with severity and age of onset. Underlying mechanism = repeats are unstable and tend to expand
