TY - JOUR
T1 - A single-nucleotide polymorphism in the EAP1 gene is associated with amenorrhea/oligomenorrhea in nonhuman primates
AU - Lomniczi, Alejandro
AU - Garcia-Rudaz, Cecilia
AU - Ramakrishnan, Ranjani
AU - Wilmot, Beth
AU - Khouangsathiene, Samone
AU - Ferguson, Betsy
AU - Dissen, Gregory A.
AU - Ojeda, Sergio R.
PY - 2012/1
Y1 - 2012/1
N2 - 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 puberty1(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.
AB - 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 puberty1(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.
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U2 - 10.1210/en.2011-1540
DO - 10.1210/en.2011-1540
M3 - Article
C2 - 22128021
AN - SCOPUS:84455188555
SN - 0013-7227
VL - 153
SP - 339
EP - 349
JO - Endocrinology
JF - Endocrinology
IS - 1
ER -