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Sepiapterin reductase (SPR) catalyzes the third step of BH4 biosynthesis. SPR gene\u2010disrupted (<jats:italic>Spr<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup>) mice exhibit a dystonic posture, low body weight, hyperphenylalaninemia, and unstable hypertension with endothelial dysfunction. In this study, we found that <jats:italic>Spr<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> mice suffered from a high incidence of severe priapism. Their erections persisted for months. The biopterin, BH4, and norepinephrine contents, and TH protein levels in the penile tissue of <jats:italic>Spr<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> mice without and with priapism were significantly reduced compared to those of <jats:italic>Spr<\/jats:italic><jats:sup>+\/+<\/jats:sup> mice. In contrast, their neural NOS (nNOS) protein levels were increased, and the cyclic guanosine monophosphate (cGMP) levels were remarkably elevated in the penises of <jats:italic>Spr<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> mice with priapism. The symptoms were relieved by repeated administration of BH4. The biopterin, BH4, and norepinephrine contents were increased in penile homogenates from BH4\u2010supplemented <jats:italic>Spr<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> mice, and the TH protein levels tended to increase, and their nitrite plus nitrate levels were significantly lower than those of vehicle\u2010treated <jats:italic>Spr<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> mice and were approximately the same as vehicle\u2010 and BH4\u2010supplemented <jats:italic>Spr<\/jats:italic><jats:sup>+\/+<\/jats:sup> mice. Thus, we deduced that the priapism of <jats:italic>Spr<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> mice is primarily caused by hypofunction of the sympathetic neurons due to cofactor depletion and the loss of TH protein and, further, dysregulation of the NO\/cGMP signaling pathway, which would be caused by disinhibition of nNOS\u2010containing neurons and\/or abnormal catabolism of cyclic nucleotides is suggested.<\/jats:p>","DOI":"10.1002\/jimd.12489","type":"journal-article","created":{"date-parts":[[2022,2,22]],"date-time":"2022-02-22T15:03:02Z","timestamp":1645542182000},"page":"621-634","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Priapism caused by partial deficiency of tetrahydrobiopterin through hypofunction of the sympathetic neurons in sepiapterin reductase gene\u2010disrupted 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