ISSN 1662-4009 (online)

ESPE Yearbook of Paediatric Endocrinology (2019) 16 7.5 | DOI: 10.1530/ey.16.7.5

ESPEYB16 7. Puberty Genetics of Puberty (3 abstracts)

7.5. EAP1 regulation of GnRH promoter activity is important for human pubertal timing

Mancini A , Howard SR , Cabrera CP , Barnes MR , David A , Wehkalampi K , Heger S , Lomniczi A , Guasti L , Ojeda SR & Dunkel L



To read the full abstract: Hum Mol Genet. 2019 Apr 15;28(8):1357–1368.

This whole-exome study from a large cohort of familial self-limited delayed puberty identifies the first EAP1 mutations leading to reduced GnRH transcriptional activity and resulting in a phenotype of self-limited delayed-puberty.

Enhanced at puberty 1 (EAP1) is a nuclear transcription factor, also called interferon regulatory factor 2 binding protein-like (IRF2BPL). Its transcriptional activity facilitates the initiation of female puberty, in a manner that is independent of hypothalamic Kiss1 expression (1). Its expression has been shown to increase in the hypothalamus of rats and non-human primates at the time of puberty, and EAP1 deficiency leads to delayed puberty and disrupted estrous cyclicity in both rodents (2) and nonhuman primates (3). EAP1 transactivates the GnRH promoter, which facilitates GnRH secretion, and inhibits the preproenkephalin promoter, which represses GnRH secretion. Despite this seemingly important role, no EAP1 mutations had been identified in humans with pubertal disorders. The authors performed whole-exome sequencing in 67 probands and 93 relatives from a large cohort of familial self-limited delayed puberty. They identified one in-frame deletion and one rare missense variant in EAP1 in two unrelated families. Using a luciferase reporter assay, EAP1 mutants showed a reduced ability to trans-activate the GnRH promoter compared to wild-type EAP1.

This study confirms the role of EAP1 in human puberty and illustrates the important role of transcriptional repressors containing Zn finger motifs in the control of GnRH secretion.

References: 1. Li C and Li P. 2017 Enhanced at puberty-1 (Eap1) expression critically regulates the onset of puberty independent of hypothalamic Kiss1 expression. Cell. Physiol. Biochem. 43: 1402–1412.

2. Heger S, Mastronardi C, Dissen GA, Lomniczi A, Cabrera R, Roth CL, Jung H, Galimi F, Sippell W, Ojeda SR. 2007 Enhanced at puberty 1 (EAP1) is a new transcriptional regulator of the female neuroendocrine reproductive axis. J. Clin. Invest. 117: 2145–2154.

3. Dissen GA, Lomniczi A, Heger S, Neff TL, Ojeda SR 2012 Hypothalamic EAP1 (enhanced at puberty 1) is required for menstrual cyclicity in nonhuman primates. Endocrinology 153: 350–361.