2. Academic Validation
  3. PAPSS2 deficiency causes androgen excess via impaired DHEA sulfation--in vitro and in vivo studies in a family harboring two novel PAPSS2 mutations

PAPSS2 deficiency causes androgen excess via impaired DHEA sulfation--in vitro and in vivo studies in a family harboring two novel PAPSS2 mutations

  • J Clin Endocrinol Metab. 2015 Apr;100(4):E672-80. doi: 10.1210/jc.2014-3556.
Wilma Oostdijk 1,  Jan Idkowiak,  Jonathan W Mueller,  Philip J House,  Angela E Taylor,  Michael W O'Reilly,  Beverly A Hughes,  Martine C de Vries,  Sarina G Kant,  Gijs W E Santen,  Annemieke J M H Verkerk,  André G Uitterlinden,  Jan M Wit,  Monique Losekoot,  Wiebke Arlt
Affiliations

Affiliation

  • 1 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.
PMID: 25594860 DOI: 10.1210/jc.2014-3556
Abstract

Context: 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.

Patients and 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.

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