Disease-Related Protein Variants of the Highly Conserved Enzyme PAPSS2 Show Marginal Stability and Aggregation in Cells.

Cellular sulfation pathways rely on the activated sulfate 3'-phosphoadenosine-5'-phosphosulfate (PAPS). In humans, PAPS is exclusively provided by the two PAPS synthases PAPSS1 and PAPSS2. Mutations found in the PAPSS2 gene result in severe disease states such as bone dysplasia, androgen excess and polycystic ovary syndrome.

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

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.

Understanding androgen action in adipose tissue.

Androgens play an important role in regulation of body fat distribution in humans. They exert direct effects on adipocyte differentiation in a depot-specific manner, via the androgen receptor (AR), leading to modulation of adipocyte size and fat compartment expansion. Androgens also impact directly on key adipocyte functions including insulin signalling, lipid metabolism, fatty acid uptake and adipokine production.