GNRH1 mutations in patients with idiopathic hypogonadotropic hypogonadism

Abstract

Idiopathic hypogonadotropic hypogonadism (IHH) is a condition characterized by failure to undergo puberty in the setting of low sex steroids and low gonadotropins. IHH is due to abnormal secretion or action of the master reproductive hormone gonadotropin-releasing hormone (GnRH). Several genes have been found to be mutated in patients with IHH, yet to date no mutations have been identified in the most obvious candidate gene, GNRH1 itself, which encodes the preprohormone that is ultimately processed to produce GnRH. We screened DNA from 310 patients with normosmic IHH (nIHH) and 192 healthy control subjects for sequence changes in GNRH1. In 1 patient with severe congenital nIHH (with micropenis, bilateral cryptorchidism, and absent puberty), a homozygous frameshift mutation that is predicted to disrupt the 3 C-terminal amino acids of the GnRH decapeptide and to produce a premature stop codon was identified. Heterozygous variants not seen in controls were identified in 4 patients with nIHH: 1 nonsynonymous missense mutation in the eighth amino acid of the GnRH decapeptide, 1 nonsense mutation that causes premature termination within the GnRH-associated peptide (GAP), which lies C-terminal to the GnRH decapeptide within the GnRH precursor, and 2 sequence variants that cause nonsynonymous amino-acid substitutions in the signal peptide and in GnRH-associated peptide. Our results establish mutations in GNRH1 as a genetic cause of nIHH.GnRH ͉ luteinizing hormone-releasing hormone ͉ LHRH

Aspectos clínicos e moleculares do hipogonadismo hipogonadotrófico isolado congênito

“…No entanto, apesar dos esforços na tentativa de identificar mutações nesse gene, apenas recentemente foram descritas as primeiras alterações no GNRH1 em pacientes com HHIn (5,74). Bouligand e cols.…”

“…A gravidade da deficiên cia gonadotrófica foi demonstrada por valores muito reduzidos de esteroides sexuais e de gonadotrofinas em ambos os indivíduos. Em outro recente estudo, a análise de 310 indivíduos com HHI normósmico revelou uma mutação em homozigose no GNRH1 em um menino com HHI congênito grave e quatro mutações em heterozigose em quatro outros pacientes com HHI (5). No entanto, o real significado das mutações identificadas em heterozigose no gene GNRH1 ainda não foi estabelecido.…”

“…Vale ressaltar que mutações de perda de função em proteínas ligantes tendem a ser menos frequentes que mutações nos seus receptores (5). Uma possibilidade para explicar essa diferença está relacionada ao tamanho do peptídeo ligante.…”

“…Além disso, o diagnóstico genético de pacientes com desenvolvimento puberal ausente ou incompleto devido à deficiência gonadotró-fica levou à identificação de novas causas genéticas associadas à etiologia do HHI (5)(6)(7)(8)(9)(10)(11). Modelos de heranças digênicas e oligogênicas da deficiência da secreção de GnRH foram descritos, frequentemente associados a fenótipos reprodutivos variáveis dentro de uma família com padrão de herança não nendeliano (4).…”

Non-syndromic congenital hypogonadotropic hypogonadism: clinical presentation and genotype–phenotype relationships

“…It was predicted to disrupt the three C-terminal amino acids of the GNRH decapeptide, and to produce a premature stop codon. The latter mutation was found in a prepubertal boy originating from Armenia who was evaluated at an age of 8 years 8 months for cryptorchidism and microphallus (127). This patient, with possible CHH and a normal sense of smell, had not entered puberty at the age of 13 years 6 months, but was subsequently virilized by testosterone enanthate treatment.…”