PAPSS2 deficiency causes androgen excess via impaired DHEA sulfation--in vitro and in vivo studies in a family harboring two novel PAPSS2 mutations.
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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DOI：
10.1210/jc.2014-3556
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发表时间：
2015-04
期刊：
影响因子：
--
通讯作者：
Arlt W
中科院分区：
文献类型：
--
作者：
Oostdijk W;Idkowiak J;Mueller JW;House PJ;Taylor AE;O'Reilly MW;Hughes BA;de Vries MC;Kant SG;Santen GW;Verkerk AJ;Uitterlinden AG;Wit JM;Losekoot M;Arlt W
PAPSS 2（PAPS synthase 2）为包括SULT 2A 1在内的所有人类磺基转移酶提供通用硫酸盐供体PAPS（3′-磷酸腺苷-5 ′-磷酸硫酸盐），负责关键雄激素前体脱氢表雄酮（DHEA）的硫酸化。受损的DHEA硫酸化被认为增加了DHEA向活性雄激素的转化，这一主张得到了先前报告的支持，该报告称一名患有失活PAPSS 2突变的女孩表现为低血清DHEA硫酸盐和雄激素过量，临床表现为阴毛早长和早发性多囊卵巢综合征。我们调查了一个家庭窝藏两个新的PAPSS 2突变，包括两个复合杂合子兄弟提出不成比例的身材矮小，低血清硫酸脱氢表雄酮，但正常的血清雄激素。患者和父母接受DHEA激发试验，包括在口服100 mg DHEA之前和之后频繁采血和收集尿液，随后通过质谱法分析DHEA硫酸化和雄激素代谢。在计算机模拟和体外研究了突变的功能影响。我们鉴定了一种新的PAPSS 2移码突变，c.1371del，p.W462Cfs*3，导致完全破坏，和一种新的错义突变，c.809G>A，p.G270D，导致DHEA硫酸化的部分破坏。患者及其母亲（p.W462Cfs*3杂合子）在基线时显示5α-还原酶活性增加，摄入DHEA后活性雄激素的产生显著增加。母亲有月经过少和慢性不排卵的病史，需要克罗米酚诱导排卵。我们提供了直接的体内证据突变PAPSS 2对DHEA硫酸化和雄激素活化的重要功能影响。PAPSS 2突变的杂合性可能与类似多囊卵巢综合征的表型相关。
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. 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. 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. 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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影响因子：
2
作者：
Warman, Matthew L.;Cormier-Daire, Valerie;Hall, Christine;Krakow, Deborah;Lachman, Ralph;LeMerrer, Martine;Mortier, Geert;Mundlos, Stefan;Nishimura, Gen;Rimoin, David L.;Robertson, Stephen;Savarirayan, Ravi;Sillence, David;Spranger, Juergen;Unger, Sheila;Zabel, Bernhard;Superti-Furga, Andrea
通讯作者：
Superti-Furga, Andrea
影响因子：
168.9
作者：
Arlt, W;Walker, EA;Shackleton, CHL
通讯作者：
Shackleton, CHL
影响因子：
5.8
作者：
Fassnacht, M;Schlenz, N;Arlt, W
通讯作者：
Arlt, W
影响因子：
30.8
作者：
Santen, Gijs W. E.;Aten, Emmelien;Kriek, Marjolein
通讯作者：
Kriek, Marjolein
DOI：
10.1016/j.bbrc.2010.04.039
发表时间：
2010-05-07
影响因子：
3.1
作者：
Grum, Daniel;van den Boom, Johannes;Mueller, Jonathan W.
通讯作者：
Mueller, Jonathan W.