A single-nucleotide polymorphism in the EAP1 gene is associated with amenorrhea/oligomenorrhea in nonhuman primates

Alejandro Lomniczi, Cecilia Garcia-Rudaz, Ranjani Ramakrishnan, Beth Wilmot, Samone Khouangsathiene, Betsy Ferguson, Gregory Dissen, Sergio Ojeda

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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 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.

Original languageEnglish (US)
Pages (from-to)339-349
Number of pages11
JournalEndocrinology
Volume153
Issue number1
DOIs
StatePublished - Jan 2012

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Oligomenorrhea
Amenorrhea
Primates
Single Nucleotide Polymorphism
Periodicity
Haplorhini
Alleles
Smad Proteins
Genes
Gene Regulatory Networks
5' Flanking Region
Menstrual Cycle
RNA Interference
Hypothalamus
Transcription Factors
Maintenance
Peptides
Incidence
Brain

ASJC Scopus subject areas

  • Endocrinology

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A single-nucleotide polymorphism in the EAP1 gene is associated with amenorrhea/oligomenorrhea in nonhuman primates. / Lomniczi, Alejandro; Garcia-Rudaz, Cecilia; Ramakrishnan, Ranjani; Wilmot, Beth; Khouangsathiene, Samone; Ferguson, Betsy; Dissen, Gregory; Ojeda, Sergio.

In: Endocrinology, Vol. 153, No. 1, 01.2012, p. 339-349.

Research output: Contribution to journalArticle

Lomniczi, Alejandro ; Garcia-Rudaz, Cecilia ; Ramakrishnan, Ranjani ; Wilmot, Beth ; Khouangsathiene, Samone ; Ferguson, Betsy ; Dissen, Gregory ; Ojeda, Sergio. / A single-nucleotide polymorphism in the EAP1 gene is associated with amenorrhea/oligomenorrhea in nonhuman primates. In: Endocrinology. 2012 ; Vol. 153, No. 1. pp. 339-349.
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