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How the function of a protein can change due
to a mutation?
The function of protein disturbed
• loss of function = reduction of the amount or activity of a protein
– Generally half of the function /activity is enough for maintenance of normal
functions (recessive)
– Not produced at all or protein is immediately degraded = null-allele
– dominant-negative effect: defective protein disturbs the function of normal
protein
• gain of function = adds the amount or activity of a protein
– Dominant change
– New function
– More active than wild type
• achondroplasia: defect in fibroblast growth factor receptor 3
– Produced more than normally
• Expressed at the wrong time during development, in wrong tissues, in
exceptionally high quantities
How a gene defect can affect the location of a protein?
What are the consequences to cell? Examples?
Wrong location if cell
– Localization signal does not work
• Protein in wrong place  function in a wrong location
• Accumulation of protein in cell  disturbs the function of other proteins
Protein-protein contact altered – How a mutation can
cause this?
Protein-protein contacts altered
– Receptor defects, e.g. LDL receptor
– Defects in cell junction proteins
– Specific mutations determines the disease and severity, e.g. mutations in
type I collagen can cause either osteoporosis, OI, EDVIIB
One gene defect can destroy the function of
many proteins - How is this possible?
• One gene defect can destroy the function of many
proteins
– N-asetylglucosamin-1-phosphotransferase phosphorylates
mannose residues in many enzymes (signal to lysosomes)
– Kinases phosphorylate several enzymes
– one subunit can bepart of several protein complexes (PDI
is a β subunit of P4H)
Chromosomal mutations
• What happens in reciprocal
translocation?
• What is Philadelphia chromosome?
• What effects can extra chromosomal
material have?
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How to find a disease gene?
• Which are the basic information needed
before the search of disease gene?
• How variation differs from mutation?
• What is candidate gene approach?
• What is the outcome of genome wide
association analysis?
Trinucleotide repeat diseases
• How repeat expands?
• Possible pathogenic mechanisms of PolyQ
repeat?
• How non-coding repeats can disturb the
function of cell/protein?
Prions –key points
• PrPSc is infectious proteinaceous agent 
no nucleic acids involved
• PrPSc can infect normal PrPC  induces
conformational change from α helix
containing molecule to β sheet containing
• Pathogenic mechanism: aggregation of
PrPSc  disturbs cell function  apoptosis
• Prion diseases are neurodegenerative
diseases causing dementia
Cancer
• What heritability in cancer mean?
• What are the hall marks of cancer?
• How mutations in proto-oncogenes and
tumorsuppressor genes can cause cancer?
Balance of proto-oncogene and tumor suppressor gene
functions
Finnish disease heritage
• What does mean Finnish disease heritage?
• Which factors affected the enrichment of
certain diseases in Finland?
• How they did that?
• Why is it useful to study rare diseases?
Treatments
• How to treat specifically a genetic disease?
• What are the possible gene therapy
approaches?