PAPSS2 deficiency causes androgen excess via impaired DHEA sulfation-in vitro and in vivo studies in a family harboring two novel PAPSS2 mutations
File(s)
Published version
Author(s)
Type
Journal Article
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.
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.
Date Issued
2015-04-01
Date Acceptance
2015-01-12
Citation
Journal of Clinical Endocrinology and Metabolism (JCEM), 2015, 100 (4), pp.E672-E680
ISSN
0021-972X
Publisher
Oxford University Press
Start Page
E672
End Page
E680
Journal / Book Title
Journal of Clinical Endocrinology and Metabolism (JCEM)
Volume
100
Issue
4
Copyright Statement
© 2015 by the Endocrine Society This article has been published under the terms of the Creative Commons Attribution License(CC-BY;https://creativecommons.org/licenses/by/4.0/),whichpermitsunrestricted use,distribution,andreproductioninanymedium,providedtheoriginalauthorandsource are credited. Copyright for this article is retained by the author(s).
License URL
Identifier
https://www.ncbi.nlm.nih.gov/pubmed/25594860
Subjects
AUTOSOMAL RECESSIVE FORM
CONVERSION
Endocrinology & Metabolism
Life Sciences & Biomedicine
ORAL DEHYDROEPIANDROSTERONE
POLYCYSTIC-OVARY-SYNDROME
Science & Technology
SPONDYLOEPIMETAPHYSEAL DYSPLASIA
Publication Status
Published
Coverage Spatial
United States
Date Publish Online
2015-04-01