A needle in a haystack: Mutations in GNRH1 as a rare cause of isolated GnRH deficiency

GNRH1, the human gene that gives rise to GnRH, has long been an obvious candidate gene for idiopathic hypogonadotropic hypogonadism, particularly because the hpg mouse, a mouse model of isolated hypogonadotropic hypogonadism, carries a deletion that disrupts Gnrh1. In 2009, 25 years after the sequence of human GNRH1 was initially determined, two groups independently reported homozygous frameshift mutations in GNRH1 in patients with idiopathic hypogonadotropic hypogonadism. In two additional families, heterozygous GNRH1 mutations segregated with reproductive disorders. In the first family, the mutation occurred alone in five female subjects with idiopathic hypogonadotropic hypogonadism, whereas in the second it co-existed with a mutation in NR0B1/DAX1 in two female subjects with delayed puberty. While hemizygous mutations the X-linked NR0B1 are a well-known cause of hypogonadotropic hypogonadism and adrenal hypoplasia in male patients, heterozygous female carriers are generally asymptomatic. Thus, mutations in GNRH1 have been associated with both mild and severe forms of GnRH deficiency, and may work in combination with other gene mutations to produce GnRH-deficient phenotypes.

► Homozygous mutations in GNRH1 are a rare cause of human isolated GnRH deficiency.
► Heterozygous mutations in GNRH1 may also contribute to isolated GnRH deficiency.
► Some heterozygous GNRH1 mutations may have dominant effects.
► GNRH1 mutations may also interact with other gene mutations to produce phenotypes.
► These findings illustrate GnRH’s essential and non-redundant role in reproduction.