Molecular and Gene Network Analysis of Thyroid Transcription Factor 1 <b><i>(TTF1)</i></b> and Enhanced at Puberty <b><i>(EAP1)</i></b> Genes in Patients with GnRH-Dependent Pubertal Disorders

Abstract

Background/Aim: TTF1 and EAP1 are transcription factors that modulate gonadotropin-releasing hormone expression. We investigated the contribution of TTF1 and EAP1 genes to central pubertal disorders. Patients and Methods: 133 patients with central pubertal disorders were studied: 86 with central precocious puberty and 47 with normosmic isolated hypogonadotropic hypogonadism. The coding region of TTF1 and EAP1 were sequenced. Variations of polyglutamine and polyalanine repeats in EAP1 were analyzed by GeneScan software. Association of TTF1 and EAP1 to genes implicated in timing of puberty was investigated by meta-network framework GeneMANIA and Cytoscape software. Results: Direct sequencing of the TTF1 did not reveal any mutation or polymorphisms. Four EAP1 synonymous variants were identified with similar frequencies among groups. The most common EAP1 5′-distal polyalanine genotype was the homozygous 12/12, but the genotype 12/9 was identified in 2 central precocious puberty sisters without functional alteration in EAP1 transcriptional activity. TTF1 and EAP1 were connected, via genetic networks, to genes implicated in the control of menarche. Conclusion: No TTF1 or EAP1 germline mutations were associated with central pubertal disorders. TTF1 and EAP1 may affect puberty by changing expression in response to other members of puberty-associated gene networks, or by differentially affecting the expression of gene components of these networks.

New Causes of Central Precocious Puberty: The Role of Genetic Factors

“…Although these case reports expanded the genotype-phenotype correlations for the kisspeptin pathways, no other CPP cases with gain-of-function mutations in KISS1R or KISS1 have been reported, suggesting that these genetic abnormalities are very rare. Other candidate genes implicated in the regulatory mechanism of GnRH secretion have also been screened (GABRA1 , NPY-Y1R , LIN28B, TAC3 , TACR3, TTF1 and EAP1) , but no pathogenic variants were identified until recently [24,25,26,27,28]. …”

Hypothalamic epigenetics driving female puberty

“…Recent evidence shows that this intercellular mechanism of excitatory vs inhibitory balance is mirrored at the genomic level. Three gene groups have emerged: as either PI genes (eg, GAD67 , PDYN , GnIH ), PA genes (eg, GnRH , GLS , KISS1 , TTF1 ) or genes with dual effects depending on hormonal milieu and cell identity (eg, TAC3 , EAP1 ).…”

“…This SNP was near the TTF1 locus, known as Nkx2.1. 84 Moreover, network connectivity analysis showed that TTF1 and EAP1 serve as central hubs to a number of genes associated with menarche, [85][86][87] including GAB2, NR4A2, ZNF462, ZNF483, TMEM18, PAX8, KDM3B, KISS1 and KISS1R (an extended gene list is provided elsewhere 69 ). These menarche-related genes are connected to two or more TRG central nodes as determined by genemania network software 88 and available databases.…”

Targeted Gene Panel Sequencing for Molecular Diagnosis of Kallmann Syndrome and Normosmic Idiopathic Hypogonadotropic Hypogonadism

“…Genomic DNA was extracted from peripheral blood leukocytes using the Gentra Puregene Blood Kit (Qiagen, Hilden, Germany). A targeted panel was designed using 69 genes that were known to be involved in hypothalamus/pituitary development [15][16][17][18][19][20][21][22][23], GnRH neuronal migration [10,11,[24][25][26][27][28][29][30][31][32][33][34], synthesis and secretion of GnRH [35][36][37][38][39][40][41][42], IGD associated neurological disorders [43][44][45][46][47][48], and rare syndromes [26,30,[49][50][51][52][53][54][55][56][57] associated with hypogonadism ( Table 1S, Supporting Information). For compreh...…”