title: The syndrome of 17,20 lyase deficiency.
abstract: BACKGROUND
  Disorders of steroidogenesis have been instrumental in delineating human steroidogenic pathways. Each genetic disorder seemed to correspond to a different steroidogenic activity, helping to identify several enzymes. Beginning in 1972, several patients have been reported as having "17,20 lyase deficiency," but there have been inconsistent genetic findings.
  
  
  OBJECTIVE
  This manuscript reviews the biochemistry, genetics, and clinical disorders of 17,20 lyase activity, which converts 21-carbon precursors of glucocorticoids to 19-carbon precursors of sex steroids.
  
  
  RESULTS
  A single enzyme, cytochrome P450c17, catalyzes both 17α-hydroxylase activity and 17,20 lyase activity. The 17,20 lyase activity is especially sensitive to the activities of the accessory proteins P450 oxidoreductase and cytochrome b(5). The first cases of genetically and biochemically proven 17,20 lyase deficiency were reported in 1997, in which specific P450c17 mutations were identified that lost 17,20 lyase activity but not 17α-hydroxylase activity when assayed in vitro. Subsequent work identified other P450c17 mutations and mutations in the genes encoding P450 oxidoreductase and cytochrome b(5). Recently, the initially reported cases from 1972 were found to carry mutations in two aldo-keto reductases, AKR1C2 and AKR1C4. These AKR1C isozymes catalyze 3α-hydroxysteroid dehydrogenase activity in the so-called "backdoor pathway" by which the fetal testis produces dihydrotestosterone without the intermediacy of testosterone.
  
  
  CONCLUSIONS
  17,20 Lyase deficiency should be considered a syndrome with multiple causes, and not a single disease. Study of this very rare disorder has substantially advanced our understanding of the pathways, mechanisms, and control of androgen synthesis. Mutations in other, as-yet unidentified genes may also cause this phenotype.
authors.affiliation: Department of Pediatrics, University of California, San Francisco, San Francisco, California 94143-0978, USA. wlmlab@ucsf.edu
authors.forename: Walter L
authors.initials: WL
authors.lastname: Miller
mesh_terms: D000312:Adrenal Hyperplasia, Congenital / Q000175:diagnosis / Q000235:genetics*; D015786:Cytochromes b5 / Q000235:genetics / Q000378:metabolism; D006801:Humans; D006913:Hydroxysteroid Dehydrogenases / Q000235:genetics / Q000378:metabolism; D008954:Models, Biological; D009154:Mutation / Q000502:physiology; D010088:Oxidoreductases / Q000235:genetics / Q000378:metabolism; D013254:Steroid 17-alpha-Hydroxylase / Q000235:genetics* / Q000378:metabolism; D013577:Syndrome; D045002:3-alpha-Hydroxysteroid Dehydrogenase (B-Specific)
chemical_list: D015786:Cytochromes b5; D006913:Hydroxysteroid Dehydrogenases; D010088:Oxidoreductases; D013254:Steroid 17-alpha-Hydroxylase; C435496:AKR1C2 protein, human; D045002:3-alpha-Hydroxysteroid Dehydrogenase (B-Specific); C048338:trans-1,2-dihydrobenzene-1,2-diol dehydrogenase
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