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

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.

Testicular Descent

“…117,118 The cumulated incidence of INSL3 gene mutations in cases with TD impairment compared to normal controls is reported to be statistically significant but relatively low (1.6-2.2%). [119][120][121] The difference is insignificant between bilateral/unilateral cases. 121 There is no definite evidence of a causal role for many of them, but they undoubtedly represent the first description of human genetic alterations related specifically to TD impairment.…”

“…[119][120][121] The difference is insignificant between bilateral/unilateral cases. 121 There is no definite evidence of a causal role for many of them, but they undoubtedly represent the first description of human genetic alterations related specifically to TD impairment. 121 In adition, INSL3 levels have been correlated with the risk of TD impairment in humans.…”

“…121 There is no definite evidence of a causal role for many of them, but they undoubtedly represent the first description of human genetic alterations related specifically to TD impairment. 121 In adition, INSL3 levels have been correlated with the risk of TD impairment in humans. 3,122 Presence of INSL3 in male cord blood suggests presence of the hormone along with testosterone during scrotal descent.…”

Serum levels of insulin-like factor 3, anti-Müllerian hormone, inhibin B, and testosterone during pubertal transition in healthy boys: a longitudinal pilot study

“…This hypertrophy of the ligament along with the growth of the fetus causes the testes to be placed at the superior end of the future inguinal canals. Functional mutations of either the INSL3 or the RXFP2 gene causes cryptorchidism in rodents as well as in humans (Nef & Parada 1999, Zimmermann et al 1999, Tomboc et al 2000, Ferlin et al 2003, 2006b, Foresta & Ferlin 2004. The later phase(s) of testicular descent are driven by androgens, although the exact mechanisms are unknown (Hutson 2013).…”

A BAC contig map over the proximal ∼3.3 Mb region of horse chromosome 21

“…The region contains a number of genes known or suspected to be associated with conditions in humans which may also be of economic significance to the equine industry. These genes include exostoses (multiple) 3 ( EXT3 ) -proposed to be associated with a bone growth disorder known as multiple exostoses (Le Merrer et al, 1994), cartilage oligomeric matrix protein ( COMP ) -associated with pseudoachondroplasia (Briggs et al, 1995;Posey et al, 2004) and insulin-like 3 ( INSL3 ) -implicated in cryptorchidism and reduced fertility in humans and mice (Nef and Parada, 1999;Zimmermann et al, 1999;Ivell et al, 2005;Ferlin et al, 2006). The development of the proposed contig will facilitate the search for such genes and/or closely linked markers associated with various genetic conditions.…”