Inactivating PAPSS2 mutations in a patient with premature pubarche.
Dehydroepiandrosterone (DHEA) sulfotransferase, known as SULT2A1, converts the androgen precursor DHEA to its inactive sulfate ester, DHEAS [corrected], thereby preventing the conversion of DHEA to an active androgen. SULT2A1 requires 3'-phosphoadenosine-5'-phosphosulfate (PAPS) for catalytic activity. We have identified compound heterozygous mutations in the gene encoding human PAPS synthase 2 (PAPSS2) in a girl with premature pubarche, hyperandrogenic anovulation, very low DHEAS levels, and increased androgen levels. In vitro coincubation of human SULT2A1 and wild-type or mutant PAPSS2 proteins confirmed the inactivating nature of the mutations. These observations indicate that PAPSS2 deficiency is a monogenic adrenocortical cause of androgen excess.
Noordam
Cees
C
Department of Pediatrics-Metabolic and Endocrine Disorders, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands.
Dhir
Vivek
V
McNelis
Joanne C
JC
Schlereth
Florian
F
Hanley
Neil A
NA
Krone
Nils
N
Smeitink
Jan A
JA
Smeets
Roel
R
Sweep
Fred C G J
FC
Claahsen-van der Grinten
Hedi L
HL
Arlt
Wiebke
W
D000728:Androgens / Q000097:blood; D000735:Androstenedione / Q000097:blood; D002648:Child; D003687:Dehydroepiandrosterone / Q000097:blood / Q000378:metabolism; D003937:Diagnosis, Differential; D005260:Female; D006579:Heterozygote; D006801:Humans; D009097:Multienzyme Complexes / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D011085:Polycystic Ovary Syndrome / Q000175:diagnosis; D011629:Puberty, Precocious / Q000097:blood / Q000235:genetics*; D012333:RNA, Messenger / Q000378:metabolism; D017422:Sequence Analysis, DNA; D013430:Sulfate Adenylyltransferase / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D015238:Sulfotransferases / Q000097:blood / Q000378:metabolism; D013739:Testosterone / Q000097:blood
D000728:Androgens; D009097:Multienzyme Complexes; D012333:RNA, Messenger; D013739:Testosterone; D000735:Androstenedione; D003687:Dehydroepiandrosterone; C022322:PAPS synthetase; D013430:Sulfate Adenylyltransferase; D015238:Sulfotransferases; C019998:dehydroepiandrosterone sulfotransferase