Species: human
Mutation name:
type: naturally occurring
fertility: subfertile
Comment: PAPSS2 deficiency causes androgen excess via impaired DHEA sulfation - in vitro and in vivo studies in a family harboring two novel PAPSS2 mutations. Oostdijk W et al. (2015) Context: PAPSS2 provides the universal sulfate donor PAPS to all human sulfotransferases including SULT2A1 responsible for sulfation of the crucial androgen precursor DHEA. Impaired DHEA sulfation is thought to increase the conversion of DHEA towards active androgens, a proposition supported by the previous report of a girl with inactivating PAPSS2 mutations, who presented with low serum DHEAS 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 DHEAS, but normal serum androgens. Patients and parents underwent a DHEA challenge test comprising frequent blood sampling and urine collection before and after 100mg 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.//////////////////

Species: mouse
Mutation name:
type: null mutation
fertility: unknown
Comment: The mouse mutation 'brachymorphic' (bm) is characterized by dome-shaped skull, short thick tail, and shortened but not widened limbs (Lane and Dickie, 1968) and has been attributed to a defective PAPS synthesis pathway (Sugahara and Schwartz, 1979). The phenotype is inherited as an autosomal recessive, and bm homozygotes breed normally, have life spans comparable to wildtype mice, and are about the same size as normals at birth. The difference in size becomes apparent over the first 4 weeks of life, resulting in a 50% reduction in limb length and a 25% reduction in axial skeletal size. The effect on growth is concomitant with a progressive reduction in size of the columnar and hypertrophic zones in the epiphyseal growth plates. Histologic and ultrastructural studies suggested defective cartilage matrix that contains normal collagen fibers, but proteoglycan aggregate granules that are smaller than normal and present in reduced numbers, particularly in the growth plate (Orkin et al., 1977).