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University of Toronto St. George
Molecular Genetics and Microbiology
Johanna Rommens

MGY470 lecture – February 5, 2013 Molecular pathology and aberrant function Mutation – evolution – of concern those that lead to pathology Wide range in mutations – Current research – mutation rates less than projected – understanding of mutation from disease situations; do not know the mutation rate – range of mutation rate per locus IS NOT CONSTANT Major factors – Clinical phenotype may be many steps away from the gene defect Loss-of-function mutations – consequences that either somehow lead to reduced protein levels, activated proteins due to muations at active site, etc. – lots of time severity of diseae reflects amount of function lost – clinical symptoms occur when get to lowest residual level Loss of function – most common in recessive disease Carriers typically do not have clinical symptoms – 50% function is suffic ient for phenotype in these individuals Enzyme deficiencies – ex,. Some metabolic diseases – need to destroy over to 90% to have clinical phenotype – Enzymopathies Haploinsufficient – one copy is not adequate Diseases – see multiple genes lead to same disease – initially when look at collection of disease – does not become obvious – becomes obvious when look at identifying number of diseases involved Ex in Fanconi’s anemia – three, four genes Outcome was identical Lysozyme – affect ability to generate low pH – number of different features impaired related to malfunctioning of this organelle Diagram demonstrating – amount of function that one sees residual – A and B – relate to recessive and dominant disease Recessive – roughly fifty percent function – B is dominant – know threshold C – haplosufficient – above fifty percent Gain of function mutations – where one has change in phenotype due to alteration or enhancement of protein function – can be done in different ways – In general – not very common Dwarfism – modulate the gene – signalling pathway remains activated – consequently, growth plates do not grow, short bones result Can lead to clog – Loss AND gain of function gene disease – RET gene – receptor Different effect depending on mutation – difficult to unravel what a mutation in a particular gene is causing EX cystic fibrosis – CFTR is the cause – transports chloride at epitheial cell surfaces – this gene is expressed in secretory tissues – at the interface between environment and body – they are the cells that line the lung, between lung and airspace, between gut and lumen – occur in sweat glands, which are ogans that excrete heat quickly by drying out water and salt and water tries to replenish own salt quickly – as sweat is excreted, body retrieves the salt back – in CF patients, salt is not taken back, leading to need for salt supplements – Nature and origins of mutations in genome Many types of mutations If balanced – translocation won’t lead to clinical phenotype Nucleotide changes – spontaneous chemical processes – cause problems with base – if repair process is not up to par – some repair systems are error-prone nucleotide substituions nonsense muations – hot spots is dinucleotide CpG – C tends to become methylated – good number of subsitutations are due to CpG methylation – in same ball park – deletions and insertions – in nucleotide level can involve bigger fragments – changes in gene dosage can be pathogenic – low copy repetitive sequences – can have non-homologous recombination – what happens if chromosome misaligns by presence of repetitive sequence – see situations where gain copy number or lose copy number – if infect gain copy number of PNP 22; if lose copy, get another disease origins of inherited mutations – differences in sex mutation rates generally speaking – all the eggs produced at birth – fidelity of polymerases high – error rate is high – enough cell division – accumulate errors – estimate 1 in 10 sperm carry deleterious mutation – number of mutations from fath
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