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AKU: From classical genetics to gene cloning

AKU: From classical genetics to gene cloning. Classical genetics Garrod - inborn errors of metabolism (1908) alkaptonuria: accumulation of homogentisic acid in urine congenital “inborn” defect rare but increased frequency with consanguinity autosomal recessive.

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AKU: From classical genetics to gene cloning

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  1. AKU: From classical genetics to gene cloning • Classical genetics • Garrod - inborn errors of metabolism (1908) • alkaptonuria: accumulation of homogentisic acid in urine • congenital “inborn” defect • rare but increased frequency with consanguinity • autosomal recessive

  2. AKU: From classical genetics to gene cloning • Biochemical genetics • Enzymatic deficiency of AKU demonstrated in 1958 • Homogentisate 1,2 dioxygenase (HGO) • Mapping • Trait mapped by homozygosity mapping and by comparative mapping (mouse gene on chr 16, sharing conserved synteny with human 3q)

  3. AKU: From classical genetics to gene cloning • Functional cloning - getting there • fungal hmgA was starting point to search human EST databse • retrieved sequence and clone • sequenced clone - encoded peptide with 52% identify with fungal hmgA • bacterially expressed protein had HGO activity • expressed in human liver and kidney

  4. AKU: From classical genetics to gene cloning • Functional cloning - proving it’s there • retrieved genomic clone • HGO mapped by somatic cell hybrid and FISH analysis - HGO maps to AKU! • mutations found in affected patients • mutant protein lacks HGO activity

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