Molecular and gene network analysis of thyroid transcription factor 1 (TTF1) and enhanced at puberty (EAP1) genes in patients with GnRH-dependent pubertal disorders.
OBJECTIVE
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.


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.


CONCLUSIONS
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.
Unidade de Endocrinologia do Desenvolvimento, Disciplina de Endocrinologia da Faculdade de Medicina da Universidade de São Paulo e Laboratório de Hormônios e Genética Molecular LIM/42, São Paulo, Brazil.
Priscilla
P
Cukier
Hollis
H
Wright
Tomke
T
Rulfs
Leticia Ferreira Gontijo
LF
Silveira
Milena Gurgel
MG
Teles
Berenice Bilharinho
BB
Mendonca
Ivo J P
IJ
Arnhold
Sabine
S
Heger
Ana Claudia
AC
Latronico
Sergio R
SR
Ojeda
Vinicius Nahime
VN
Brito
D002648:Child; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics*; D005838:Genotype; D018095:Germ-Line Mutation; D007987:Gonadotropin-Releasing Hormone; D006801:Humans; D007006:Hypogonadism / Q000235:genetics / Q000378:metabolism; D008297:Male; D064249:Securin / Q000096:biosynthesis / Q000235:genetics; D014157:Transcription Factors
D004268:DNA-Binding Proteins; D064249:Securin; C504003:TTF1 protein, human; D014157:Transcription Factors; C578002:pituitary tumor-transforming protein 1, human; D007987:Gonadotropin-Releasing Hormone