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.

Fig. 1.

Features of patient 1, who has a homozygous frameshift mutation in GNRH1. (A) Pedigree. Arrow, proband. (B) Testicular biopsy of patient 1, stained with hematoxylin and eosin. [Magnification: 1,000×.] Arrows, gonocyte-like cells; asterisks, interstitial cells.

Fig. 2.

Pedigrees of patients with nIHH found to have heterozygous sequence variants in GNRH1. Arrows, probands; +, wild type.

Fig. 3.

Sequence variants in GNRH1 identified in patients with nIHH. (A) Genomic structure of GNRH1. Purple boxes, coding regions of exons; green boxes, noncoding regions of exons; narrow blue lines, introns; thick blue line, a variant intron within the first exon. (B) Alignment of amino-acid sequences of the GnRH preprohormone from 4 mammalian species and the peptide sequence predicted to be produced by the G29GfsX12 mutation of patient 1. Yellow, Region processed to produce the GnRH decapeptide; gray, region that gives rise to the GAP; red, amino acids altered by G29GfsX12 (with premature stop codon indicated by an asterisk); asterisks below, amino acids altered by sequence variants in GNRH1. (C) Sequence traces indicating base-pair changes (arrows).