title: PAPSS2 deficiency causes androgen excess via impaired DHEA sulfation--in vitro and in vivo studies in a family harboring two novel PAPSS2 mutations.
abstract: BACKGROUND
  PAPSS2 (PAPS synthase 2) provides the universal sulfate donor PAPS (3'-phospho-adenosine-5'-phosphosulfate) to all human sulfotransferases, including SULT2A1, responsible for sulfation of the crucial androgen precursor dehydroepiandrosterone (DHEA). Impaired DHEA sulfation is thought to increase the conversion of DHEA toward active androgens, a proposition supported by the previous report of a girl with inactivating PAPSS2 mutations who presented with low serum DHEA sulfate and androgen excess, clinically manifesting with premature pubarche and early-onset polycystic ovary syndrome.
  
  
  METHODS
  We investigated a family harboring two novel PAPSS2 mutations, including two compound heterozygous brothers presenting with disproportionate short stature, low serum DHEA sulfate, but normal serum androgens. Patients and parents underwent a DHEA challenge test comprising frequent blood sampling and urine collection before and after 100 mg DHEA orally, with subsequent analysis of DHEA sulfation and androgen metabolism by mass spectrometry. The functional impact of the mutations was investigated in silico and in vitro.
  
  
  RESULTS
  We identified a novel PAPSS2 frameshift mutation, c.1371del, p.W462Cfs*3, resulting in complete disruption, and a novel missense mutation, c.809G>A, p.G270D, causing partial disruption of DHEA sulfation. Both patients and their mother, who was heterozygous for p.W462Cfs*3, showed increased 5α-reductase activity at baseline and significantly increased production of active androgens after DHEA intake. The mother had a history of oligomenorrhea and chronic anovulation that required clomiphene for ovulation induction.
  
  
  CONCLUSIONS
  We provide direct in vivo evidence for the significant functional impact of mutant PAPSS2 on DHEA sulfation and androgen activation. Heterozygosity for PAPSS2 mutations can be associated with a phenotype resembling polycystic ovary syndrome.
authors.affiliation: Department of Pediatrics (W.O., M.C.d.V., J.M.W.), Leiden University Medical Center, 2300 RC Leiden, The Netherlands; Centre for Endocrinology, Diabetes, and Metabolism (J.I., J.W.M., P.J.H., A.E.T., M.W.O., B.A.H., W.A.), School of Clinical and Experimental Medicine, University of Birmingham, Birmingham B15 2TT, United Kingdom; Department of Clinical Genetics (S.G.K., G.W.E.S., M.L.), Leiden University Medical Center, 2300 RC Leiden, The Netherlands; and Department of Internal Medicine (A.J.M.H.V., A.G.U.), Erasmus Medical Center Rotterdam, 3000 CA Rotterdam, The Netherlands.
authors.forename: Wilma
authors.initials: W
authors.lastname: Oostdijk
authors.forename: Jan
authors.initials: J
authors.lastname: Idkowiak
authors.forename: Jonathan W
authors.initials: JW
authors.lastname: Mueller
authors.forename: Philip J
authors.initials: PJ
authors.lastname: House
authors.forename: Angela E
authors.initials: AE
authors.lastname: Taylor
authors.forename: Michael W
authors.initials: MW
authors.lastname: O'Reilly
authors.forename: Beverly A
authors.initials: BA
authors.lastname: Hughes
authors.forename: Martine C
authors.initials: MC
authors.lastname: de Vries
authors.forename: Sarina G
authors.initials: SG
authors.lastname: Kant
authors.forename: Gijs W E
authors.initials: GW
authors.lastname: Santen
authors.forename: Annemieke J M H
authors.initials: AJ
authors.lastname: Verkerk
authors.forename: André G
authors.initials: AG
authors.lastname: Uitterlinden
authors.forename: Jan M
authors.initials: JM
authors.lastname: Wit
authors.forename: Monique
authors.initials: M
authors.lastname: Losekoot
authors.forename: Wiebke
authors.initials: W
authors.lastname: Arlt
mesh_terms: D000293:Adolescent; D000328:Adult; D000728:Androgens / Q000378:metabolism*; D003687:Dehydroepiandrosterone / Q000378:metabolism*; D019314:Dehydroepiandrosterone Sulfate / Q000378:metabolism; D005190:Family; D005260:Female; D006801:Humans; D017588:Hyperandrogenism / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009097:Multienzyme Complexes / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D013430:Sulfate Adenylyltransferase / Q000235:genetics* / Q000378:metabolism; D013431:Sulfates / Q000378:metabolism*; D055815:Young Adult
chemical_list: D000728:Androgens; D009097:Multienzyme Complexes; D013431:Sulfates; D003687:Dehydroepiandrosterone; D019314:Dehydroepiandrosterone Sulfate; C022322:PAPS synthetase; D013430:Sulfate Adenylyltransferase