title: A single-nucleotide polymorphism in the EAP1 gene is associated with amenorrhea/oligomenorrhea in nonhuman primates.
abstract: Current evidence suggests that the acquisition of female reproductive capacity and the maintenance of mature reproductive function are related processes transcriptionally regulated by gene networks operating within the neuroendocrine brain. One of these genes, termed enhanced at puberty 1 (EAP1), encodes an upstream regulator of these processes. Selective inhibition of EAP1 expression in discrete regions of the rat and nonhuman primate (NHP) hypothalamus, via targeted delivery of RNA interference, either disrupts (rats) or abolishes (monkeys) reproductive cycles. 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'-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 TGFβ1, 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.
authors: Division of Neuroscience, Oregon National Primate Research Center, Oregon Health and Science University, Neuroscience, 505 NW 185th Avenue, Beaverton, Oregon 97006, USA. lomniczi@ohsu.edu
authors: Alejandro
authors: A
authors: Lomniczi
authors: Cecilia
authors: C
authors: Garcia-Rudaz
authors: Ranjani
authors: R
authors: Ramakrishnan
authors: Beth
authors: B
authors: Wilmot
authors: Samone
authors: S
authors: Khouangsathiene
authors: Betsy
authors: B
authors: Ferguson
authors: Gregory A
authors: GA
authors: Dissen
authors: Sergio R
authors: SR
authors: Ojeda
mesh_terms: D024506:5' Flanking Region; D000568:Amenorrhea / Q000235:genetics / Q000503:physiopathology / Q000662:veterinary*; D000818:Animals; D001483:Base Sequence; D001665:Binding Sites / Q000235:genetics; D017931:DNA Primers / Q000235:genetics; D005260:Female; D055785:Gene Knockdown Techniques; D015810:Linkage Disequilibrium; D008253:Macaca mulatta / Q000235:genetics* / Q000502:physiology; D008597:Menstrual Cycle / Q000235:genetics / Q000502:physiology; D008992:Monkey Diseases / Q000235:genetics* / Q000503:physiopathology; D009839:Oligomenorrhea / Q000235:genetics / Q000503:physiopathology / Q000662:veterinary*; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D051900:Smad3 Protein / Q000378:metabolism; D015533:Transcriptional Activation / Q000187:drug effects; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology
chemical_list: D017931:DNA Primers; D051900:Smad3 Protein; D053773:Transforming Growth Factor beta1