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Genetic insights into human isolated gonadotropin deficiency

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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.

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Acknowledgment

This work was supported in part by grants from Fundação de Amparo à Pesquisa do Estado de São Paulo—FAPESP (to ACL, process number: 05/04726-0) and Conselho Nacional de Desenvolvimento Científico e Tecnológico—CNPq (to ACL, process number: 300469/2005-5)

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  1. Developmental Endocrinology Unit, Hormone and Molecular Genetic Laboratory LIM/42, Clinical Hospital, São Paulo University Medical School, Sao Paulo, 05403-900, Brazil

    Ericka Barbosa Trarbach, Leticia Gontijo Silveira & Ana Claudia Latronico

  2. Disciplina de Endocrinologia e Metabologia, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, Av. Dr. Enéas de Carvalho Aguiar, 155—2° andar Bloco 6, Sao Paulo, SP, 05403-900, Brazil

    Ana Claudia Latronico

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  1. Ericka Barbosa Trarbach
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  2. Leticia Gontijo Silveira
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Correspondence to Ana Claudia Latronico.

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Trarbach, E.B., Silveira, L.G. & Latronico, A.C. Genetic insights into human isolated gonadotropin deficiency. Pituitary 10, 381–391 (2007). https://doi.org/10.1007/s11102-007-0061-7

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