Insulin-like factor 3 gene mutations in testicular dysgenesis syndrome: Clinical and functional characterization

A. Ferlin, Natalia Bogatcheva, L. Gianesello, A. Pepe, C. Vinanzi, A. I. Agoulnik, Carlo Foresta

Research output: Contribution to journalArticle

48 Citations (Scopus)

Abstract

Insulin-like factor 3 (INSL3) plays a crucial role in testicular descent. Genetic ablation of Insl3 or its G protein-coupled receptor, leucine-rich repeat-containing G-protein-coupled receptor (Lgr8), causes cryptorchidism in mice. Mutation analyses of INSL3 in humans showed an association with cryptorchidism but led to non-conclusive data about a causative role. In this study, we explored the hypothesis that mutations in INSL3 may be associated with the signs of testicular dysgenesis syndrome (TDS). We screened for mutations in INSL3 gene in 967 subjects with a history of maldescended testes and/or infertility and/or testicular cancer and in 450 controls. Furthermore, we carried out in vitro functional analysis of three novel mutations by analysis of INSL3-dependent cAMP increase in cells expressing LGR8. We found six INSL3 mutations in 18 of 967 patients (1.9%) and no mutations in controls. Prevalence of mutations was similar in the different groups of patients (cryptorchidism and/or infertility and/testicular cancer). Three mutations were novel findings (R4H, W69R, and R72K); however, their analysis showed normal cAMP increase after the activation of LGR8 receptor. In conclusion, we found a significant association of INSL3 gene mutations in men presenting one or more signs of TDS syndrome. However, a causative role for some of these mutations is not clearly supported by functional analyses. Although a role for mutations of INSL3 and LGR8 genes in cryptorchidism is reasonable, additional studies are needed to establish an association between the disruption of INSL3 pathway and higher risk of infertility or testicular cancer.

Original languageEnglish (US)
Pages (from-to)401-406
Number of pages6
JournalMolecular Human Reproduction
Volume12
Issue number6
DOIs
StatePublished - Jun 2006
Externally publishedYes

Fingerprint

Insulin
Mutation
Genes
Cryptorchidism
Testicular Neoplasms
Infertility
G-Protein-Coupled Receptors
Leucine
Testis

Keywords

  • Cryptorchidism
  • INSL3
  • LGR8
  • Male infertility
  • Testicular cancer

ASJC Scopus subject areas

  • Obstetrics and Gynecology
  • Genetics
  • Developmental Biology
  • Embryology
  • Cell Biology

Cite this

Insulin-like factor 3 gene mutations in testicular dysgenesis syndrome : Clinical and functional characterization. / Ferlin, A.; Bogatcheva, Natalia; Gianesello, L.; Pepe, A.; Vinanzi, C.; Agoulnik, A. I.; Foresta, Carlo.

In: Molecular Human Reproduction, Vol. 12, No. 6, 06.2006, p. 401-406.

Research output: Contribution to journalArticle

Ferlin, A. ; Bogatcheva, Natalia ; Gianesello, L. ; Pepe, A. ; Vinanzi, C. ; Agoulnik, A. I. ; Foresta, Carlo. / Insulin-like factor 3 gene mutations in testicular dysgenesis syndrome : Clinical and functional characterization. In: Molecular Human Reproduction. 2006 ; Vol. 12, No. 6. pp. 401-406.
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