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The striking loss of menstrual cyclicity resulting from knocking down hypothalamic EAP1 expression suggests that diminished EAP1 function may contribute to disorders of the menstrual cycle of neuroendocrine origin. Here we show that a single-nucleotide polymorphism in the 5\u2032-flanking region of EAP1 gene is associated with increased incidence of amenorrhea\/oligomenorrhea in NHP. In the presence of the risk allele, binding of the transcription factor mothers against decapentaplegic homolog 3 (SMAD3) to its recognition site contained within the polymorphic sequence in the monkey EAP1 promoter is reduced. The risk allele also diminishes the increase in EAP1 promoter activity elicited by TGF\u03b21, a peptide that activates a SMAD3\/4-mediated signaling pathway to regulate gene transcription. These findings indicate that common genetic variation in the EAP1 locus increases the susceptibility of NHP to loss\/disruption of menstrual cyclicity. They also raise the possibility that polymorphisms in EAP1 may increase the risk of functional hypothalamic amenorrhea in humans.<\/jats:p>","DOI":"10.1210\/en.2011-1540","type":"journal-article","created":{"date-parts":[[2011,12,1]],"date-time":"2011-12-01T09:28:30Z","timestamp":1322731710000},"page":"339-349","source":"Crossref","is-referenced-by-count":21,"title":["A Single-Nucleotide Polymorphism in the EAP1 Gene Is Associated with Amenorrhea\/Oligomenorrhea in Nonhuman Primates"],"prefix":"10.1210","volume":"153","author":[{"given":"Alejandro","family":"Lomniczi","sequence":"first","affiliation":[{"name":"Division of Neuroscience (A.L., C.G.-R., G.A.D., S.R.O.), Beaverton, Oregon 97006"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cecilia","family":"Garcia-Rudaz","sequence":"first","affiliation":[{"name":"Division of Neuroscience (A.L., C.G.-R., G.A.D., S.R.O.), Beaverton, Oregon 97006"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ranjani","family":"Ramakrishnan","sequence":"first","affiliation":[{"name":"Primate Genetics Program (R.R., S.K., B.F.), Oregon National Primate Research Center, Beaverton, Oregon 97006"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Beth","family":"Wilmot","sequence":"first","affiliation":[{"name":"Division of Bioinformatics and Computational Biology (B.W.), Department of Medical Informatics and Clinical Epidemiology and the Oregon Clinical and Translational Research Institute, Oregon Health and Science University, Beaverton, Oregon 97006"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Samone","family":"Khouangsathiene","sequence":"first","affiliation":[{"name":"Primate Genetics Program (R.R., S.K., B.F.), Oregon National Primate Research Center, Beaverton, Oregon 97006"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Betsy","family":"Ferguson","sequence":"first","affiliation":[{"name":"Primate Genetics Program (R.R., S.K., B.F.), Oregon National Primate Research Center, Beaverton, Oregon 97006"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gregory A.","family":"Dissen","sequence":"first","affiliation":[{"name":"Division of Neuroscience (A.L., C.G.-R., G.A.D., S.R.O.), Beaverton, Oregon 97006"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sergio R.","family":"Ojeda","sequence":"first","affiliation":[{"name":"Division of Neuroscience (A.L., C.G.-R., G.A.D., S.R.O.), Beaverton, Oregon 97006"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"80","reference":[{"key":"2020071612432483300_B1","doi-asserted-by":"crossref","first-page":"2145","DOI":"10.1172\/JCI31752","article-title":"Enhanced at puberty 1 (EAP1) is a new transcriptional regulator of the female neuroendocrine reproductive axis.","volume":"117","author":"Heger","year":"2007","journal-title":"J Clin Invest"},{"key":"2020071612432483300_B2","doi-asserted-by":"crossref","first-page":"350","DOI":"10.1210\/en.2011-1541","article-title":"Hypothalamic EAP1 (enhanced at puberty 1) is required for menstrual cyclicity in nonhuman primates","volume":"153","author":"Dissen","journal-title":"Endocrinology"},{"key":"2020071612432483300_B3","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1016\/S0889-8529(18)30179-8","article-title":"Female hypogonadotropic hypogonadism. 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