Abstract | CONTEXT: 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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Authors | Wilma Oostdijk, 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 |
Journal | The Journal of clinical endocrinology and metabolism
(J Clin Endocrinol Metab)
Vol. 100
Issue 4
Pg. E672-80
(Apr 2015)
ISSN: 1945-7197 [Electronic] United States |
PMID | 25594860
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Androgens
- Multienzyme Complexes
- Sulfates
- Dehydroepiandrosterone
- Dehydroepiandrosterone Sulfate
- PAPS synthetase
- Sulfate Adenylyltransferase
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Topics |
- Adolescent
- Adult
- Androgens
(metabolism)
- Dehydroepiandrosterone
(metabolism)
- Dehydroepiandrosterone Sulfate
(metabolism)
- Family
- Female
- Humans
- Hyperandrogenism
(genetics, metabolism)
- Male
- Middle Aged
- Multienzyme Complexes
(genetics, metabolism)
- Mutation
- Sulfate Adenylyltransferase
(genetics, metabolism)
- Sulfates
(metabolism)
- Young Adult
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