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This version published online on March 28, 2006
Journal of Clinical Endocrinology & Metabolism, doi:10.1210/jc.2005-2657
A more recent version of this article appeared on June 1, 2006
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Submitted on December 9, 2005
Accepted on March 20, 2006

Allelic Variants of the GABA-A Receptor {alpha}-1 Subunit Gene (GABRA1) are not Associated with Idiopathic Gonadotropin-Dependent Precocious Puberty in Girls with and without Electroencephalographic Abnormalities

Vinicius Nahime Brito*, Berenice Bilharinho Mendonca, Laura M F F Guilhoto, Karina Cocco Monteiro Freitas, Ivo J Prado Arnhold, and Ana Claudia Latronico

Unidade de Endocrinologia do Desenvolvimento e Laboratório de Hormônios e Genética Molecular LIM/42, Disciplina de Endocrinologia e Metabologia and Seção de Eletroencefalografia da Divisão de Clínica Neurológica, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo

* To whom correspondence should be addressed. E-mail: vinbrito{at}uol.com.br.

Context The {gamma}-aminobutyric acid (GABA) is a dominant inhibitory neurotransmitter involved in the modulation of brain electric activity and puberty onset in primates. GABA inhibitory effects on GnRH neurons are mainly mediated by GABA-A receptor {alpha}-1 subunit.

Objective To investigate functional mutations or polymorphisms of the GABA-A receptor {alpha}-1 subunit (GABRA1) in girls with idiopathic gonadotropin-dependent precocious puberty (GDPP) with and without electroencephalographic (EEG) abnormalities.

Design The entire coding region of GABRA1 was sequenced in all patients. Two known GABRA1 polymorphisms were investigated by GeneScan software analysis or enzymatic restriction. Seventy-three normal women were used as controls for genetic study. EEG tracings were recorded in 23 girls with GDPP and 17 girls with adequate pubertal development.

Setting University Hospital

Patients Thirty-one girls from 28 unrelated families with idiopathic GDPP.

Results Automatic sequencing revealed no functional mutations in girls with GDPP. Seven different GABRA1 polymorphisms, including two exonic (156T > C and 1323G > A) and 5 intronic (IVS2-712(GT)n, IVS3 + 12A > T, IVS8 + 45T > G, IVS9 + 76A > G and IVS10 + 15G > A), were found in GDPP girls and controls. Abnormal EEG tracings were found in 26% of 23 girls with GDPP, 2 of them with epilepsy. Genotype and allele frequencies of the GABRA1 polymorphisms were not statistically different between unrelated GDPP girls and controls as well as between GDPP girls with or without EEG abnormalities.

Conclusions GABRA1 functional mutations or polymorphisms are not associated with the intrinsic mechanism of GDPP in girls with and without EEG abnormalities.
Key words: GnRH secretion • GABA • GABRA1 • precocious puberty • epilepsy • EEG






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