Genetic insights into human isolated gonadotropin deficiency

Abstract

The identification of naturally occurring genetic mutations has provided unique insight into the current knowledge of the human hypothalamic-pituitary-gonadal axis. In the past decade, several monogenic causes have been reported in patients with isolated gonadotropin deficiency. Kallmann Syndrome is a clinically and genetically heterogeneous disorder, characterized by isolated hypogonadotropic hypogonadism and anosmia or hyposmia. To date, loss-of-function mutations in the genes encoding anosmin-1 (KAL1) and fibroblast growth factor receptor 1 (FGFR1) have been described in the X-linked and autosomal dominant forms of this syndrome, respectively. More recently, several heterozygous, homozygous or compound heterozygous mutations in the G protein-coupled prokineticin receptor-2 (PROKR2) and one of its ligands, prokineticin-2 (PROK2) were described in Kallmann syndrome. In addition, complex genetic transmission (digenic inheritance) was recently demonstrated in this condition. Regarding isolated hypogonadotropic hypogonadism without olfactory abnormalities, loss-of-function mutations in the Gonadotropin-releasing hormone (GnRH) receptor (GnRH-R) or the G-protein coupled receptor 54 (GPR54) genes, both encoding transmembrane receptors, have been described, as well as FGFR1 mutations. Finally, mutations of the beta sub-units of LH and FSH have been described in patients with selective gonadotropin deficiency. We review the role of these distinct genetic factors in human isolated hypogonadotropic hypogonadism.

Aspectos clínicos e moleculares do hipogonadismo hipogonadotrófico isolado congênito

“…Esse foi o primeiro gene autossômico relacionado ao surgimento do hipogonadismo hipogonadotrófico em humanos (8). As mutações no FGFR1 têm sido encontradas numa prevalência de 10%-17%, tanto na sín-drome de Kallmann quanto no hipogonadismo hipogonadotrófico normósmico (37). A maior parte dessas mutações foi identificada em heterozigose, sendo representada por pequenas deleções/inserções de base e mutações de ponto (37).…”

“…As mutações no FGFR1 têm sido encontradas numa prevalência de 10%-17%, tanto na sín-drome de Kallmann quanto no hipogonadismo hipogonadotrófico normósmico (37). A maior parte dessas mutações foi identificada em heterozigose, sendo representada por pequenas deleções/inserções de base e mutações de ponto (37). Até o momento, existe apenas o relato de uma paciente com hipogonadismo hipogonadotrófico e olfato normal causado por uma deleção em heterozigose completa do gene FGFR1 (38).…”

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

“…In the last two decades, CHH has gradually been classified on the basis of genetic and pathophysiological features (2, 3, [15][16][17]. Grossly speaking, CHH is now divided into forms secondary to developmental abnormalities (ontogenesis) of the gonadotropin axis, and especially GNRH neurons.…”

Rites of passage through puberty: A complex genetic ensemble

“…No clear hormonal or metabolic trigger has been identified as a switch that activates the hypothalamic gonadotropin-releasing hormone (GnRH) pulse generator (1). Instead, genetic abnormalities that preclude puberty have provided the major insights into the pathways that are critical for the development and maturation of the reproductive axis (2,3). Perhaps the best candidate for regulating the onset of puberty is kisspeptin, the ligand for the receptor encoded by GPR54, a gene identified as a cause of recessive hypogonadotropic hypogonadism (4,5).…”

“…Subsequent studies, however, identified KAL1 mutations in a minority of patients with familial or sporadic forms of IHH (2,3). Moreover, pedigrees with clear-cut autosomal dominant and recessive patterns of transmission suggested the involvement of other genes (11).…”