PAPSS2 deficiency causes androgen excess via impaired DHEA sulfation–in vitro and in vivo studies in a family harboring two novel PAPSS2 mutations
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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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PAPSS2 mutations clinically result in androgen excess manifesting with premature pubarche and a phenotype in women resembling polycystic ovary syndrome (PCOS), also observed in heterozygous carriers of major loss-of-function mutations.
“Clinically this results in androgen excess manifesting with premature pubarche and a phenotype in women resembling polycystic ovary syndrome (PCOS), also observed in heterozygous carriers of major loss-of-function mutations (Noordam et al., 2009, Oostdijk et al., 2015).”
From Intracrine androgen biosynthesis, metabolism and action revisited (2018) · cites this paper as Oostdijk et al., 2015
Mutations of PAPSS2 lead to impaired PAPS synthesis and thus impaired sulfation, which results in enhanced conversion of DHEA to active androgens.
“Mutations of PAPS synthase type 2 (PAPSS2) lead to impaired PAPS synthesis and thus impaired sulfation, which results in enhanced conversion of DHEA to active androgens.”
From Intracrine androgen biosynthesis, metabolism and action revisited (2018) · cites this paper as Oostdijk et al., 2015
Inactivating mutations in the PAPSS2 gene are associated with premature puberty, hyperandrogenism, and anovulation, with reduced DHEAS and elevated androgen levels.
“Inactivating mutations in PAPSS2 gene are associated with premature puberty, hyperandrogenism, and anovulation, with reduced DHEAS and elevated androgens levels.”
From Classic and current concepts in adrenal steroidogenesis: a reappraisal (2022) · cites this paper as [29]
PAPSS2 deficiency is characterized as a monogenic cause of excess adrenal androgens.
“Thus, PAPSS2 deficiency is characterized as a monogenic cause of excess adrenal androgens ( 29 , 30 ).”
From Classic and current concepts in adrenal steroidogenesis: a reappraisal (2022) · cites this paper as [29]
SULT2A1 converts the androgen precursor DHEA into its sulfate ester DHEAS, which is inactive, preventing conversion of DHEA into active androgens and possible hyperandrogenism.
“The SULT2A1 enzyme (DHEA sulfotransferase) converts the androgen precursor DHEA into its sulfate ester DHEAS, which is inactive ( Figure 1 ). This reaction prevents conversion of DHEA into active androgens escaping possible hyperandrogenism.”
From Classic and current concepts in adrenal steroidogenesis: a reappraisal (2022) · cites this paper as [29]
The catalytic action of SULT2A1 requires PAPS synthase 2 (PAPSS2), an efficient sulfate donor.
“Also, the catalytic action of SULT2A1 requires PAPS (3’-phosphoadenosine-5’-phosphosulfate) synthase 2 (PAPSS2), an efficient sulfate donor.”
From Classic and current concepts in adrenal steroidogenesis: a reappraisal (2022) · cites this paper as [29]
After an oral DHEA challenge, two brothers with compound heterozygous PAPSS2 mutations and their mother exhibited a subnormal rate of DHEAS generation, whereas DHEA generation and urinary androgen excretion increased.
“After an oral DHEA challenge, the brothers and their mother exhibited a subnormal rate of DHEAS generation, whereas DHEA generation and urinary androgen excretion increased, with evidence of increased 5α-reductase activity (Table 2) in the affected brothers and their mother (89).”
From Steroid Metabolome Analysis in Disorders of Adrenal Steroid Biosynthesis and Metabolism (2019) · cites this paper as [89]
The mother of the first reported PAPSS2 case and the mother of the two brothers were carriers of major loss-of-function PAPSS2 mutations and presented clinically with PCOS.
“Of note, this mother and the mother of the first reported case were carriers of major loss-of-function PAPSS2 mutations and presented clinically with PCOS.”
From Steroid Metabolome Analysis in Disorders of Adrenal Steroid Biosynthesis and Metabolism (2019) · cites this paper as [89]
The affected brothers with PAPSS2 deficiency and their mother showed evidence of increased 5α-reductase activity after oral DHEA challenge.
“After an oral DHEA challenge, the brothers and their mother exhibited a subnormal rate of DHEAS generation, whereas DHEA generation and urinary androgen excretion increased, with evidence of increased 5α-reductase activity (Table 2) in the affected brothers and their mother (89).”
From Steroid Metabolome Analysis in Disorders of Adrenal Steroid Biosynthesis and Metabolism (2019) · cites this paper as [89]
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- Authors
- Oostdijk, W., Idkowiak, J., Mueller, J. W., House, P. J., Taylor, A. E., O'Reilly, M. W., Hughes, B. A., de Vries, M. C., Kant, S. G., Santen, G. W. E., Verkerk, A. J. M. H., Uitterlinden, A. G., Wit, J. M., Losekoot, M., & Arlt, W.
- Affiliations
- Leiden University Medical Center (NL)
- University of Birmingham (GB)
- 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 Pediatrics (W.O., M.C.d.V., J.M.W.), Leiden University Medical Center, 2300 RC Leiden, The Netherlands
- Erasmus MC (NL)
- Corresponding author
- Arlt, Wiebke
- ORCID
- Venue
- The Journal of Clinical Endocrinology & Metabolism
- Publisher
- The Endocrine Society
- Published
- 2015-04-01
- Volume
- 100
- Issue
- 4
- Pages
- E672-E680
- ISSN
- 0021-972X (ISSN-L)
- 1945-7197
- PMC
- PMC4399300
- OpenAlex
- W2127237435
- Cited by
- 81
- References
- 25
- Citations by year
- 2026: 4 · 2025: 2 · 2024: 6 · 2023: 6 · 2022: 5 · 2021: 8 · 2020: 4 · 2019: 10 · 2018: 7 · 2017: 8 · 2016: 11 · 2015: 9 · 2014: 1
- FWCI
- 5.07
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- The Journal of Clinical Endocrinology & Metabolism (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion, other-oa)
- RePub (Erasmus University Rotterdam) (submittedVersion, other-oa)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Leiden Repository (Leiden University) (submittedVersion)
- University of Birmingham Research Portal (University of Birmingham) (submittedVersion, cc-by)
- Spiral (Imperial College London) (submittedVersion, cc-by)
- Funders
- Wellcome Trust (099909, 092283)
- European Commission (625451)
- Novo Nordisk
- Medical Research Council (G1001964)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sexual Differentiation and Disorders
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
- Health Sciences › Medicine › Reproductive Medicine › Ovarian function and disorders
- Keywords
- PAPSS2, hyperandrogenism, polycystic ovary syndrome, 5alpha-reductase activity, frameshift mutation, missense mutations, heterozygosity, premature pubarche, short stature, DHEA sulfate, SULT2A1, androgen metabolism
- MeSH terms
- Adolescent, Adult, Androgens, Dehydroepiandrosterone, Family, Female, Humans, Male, Middle Aged, Multienzyme Complexes, Mutation, Sulfate Adenylyltransferase, Sulfates, Hyperandrogenism, Dehydroepiandrosterone Sulfate, Young Adult
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