Novel Mutations Involving the INSL3 Gene Associated With Cryptorchidism

Abstract

Mutations involving the insulin-like factor 3 gene may contribute to other anomalies of male genital development, such as micropenis.

Morphogenetic Targets and Genetics of Undescended Testis

“…Thus, the Thr allele may constitute a recessive susceptibility factor for the cryptorchidism development [Yamazawa et al, 2007]. However, such positive association between cryptorchidism and Ala60Thr polymorphism has not been identified in the other studies [Koskimies et al, 2000;Krausz et al, 2000;Tomboc et al, 2000;Lim et al, 2001;Marin et al, 2001b;Takahashi et al, 2001;Baker et al, 2002;Ferlin et al, 2003;El Houate et al, 2007]. Thus, although Thr/Thr genotype was frequent in the cryptorchid patients analyzed by Yamazawa et al [2007], it is unlikely that the Thr/Thr genotype constitutes a marked susceptibility factor for cryptorchidism that can yield positive asso ciation in multiple case-control studies.…”

“…However, it has to be considered that many of these mutations are located in the C-peptide that is normally excised during processing of the preprohormone, and molecular modeling and comparative analyses of protein sequences in most cases revealed the importance of the mutated amino acids. The novel substitution C-19G in the promoter region could be interesting, but expression analysis of promoter activity did not reveal any difference with respect to WT INSL3 [El Houate et al, 2007]. In LGR8 gene, the Thr222Pro mutation [Gorlov et al, 2002;Hsu et al, 2002;Ferlin et al, 2003], which represents by far the most frequent mutation of this gene, apparently compromises the INSL3 signaling in vitro.…”

“…Foresta et al [2008] recently reviewed the published data on the INSL3 and LGR8 genes regarding cryptorchidism development. Mutations in these 2 loci have been analyzed in 15 and 7 studies, respectively, including more than 1,500 and almost 1,000 patients with cryptorchidism, respectively, and similar numbers of controls [Koskimies et al, 2000;Krausz et al, 2000;Tomboc et al, 2000;Lim et al, 2001;Marin et al, 2001a, b;Takahashi et al, 2001;Baker et al, 2002;Gorlov et al, 2002;Canto et al, 2003;Ferlin et al, 2003Ferlin et al, , 2006Roh et al, 2003;Feng et al, 2004;Foresta and Ferlin, 2004;Bogatcheva et al, 2007;El Houate et al, 2007;Yamazawa et al, 2007]. Some mutations have been found in both controls and patients and are therefore considered as normal variants, whereas other mutations are detected only in cases [Foresta et al, 2008].…”

“…In particular, evidence of the inability or reduced ability of the mutated peptide to activate LGR8 exists only for Val18Met and Pro49Ser mutations in INSL3 [Bogatcheva et al, 2003;El Houate et al, 2007]. Strong evidence also exists for the Arg73X mutation that results in the termination of translation.…”

“…Strong evidence also exists for the Arg73X mutation that results in the termination of translation. Weaker evidence exists for Arg102Cys [Bogatcheva et al, 2003], whereas normal activation of the receptor was observed with Trp69Arg [Ferlin et al, 2006], Pro93Leu [Bogatcheva et al, 2003], Arg102His [Bogatcheva et al, 2003], Arg105His [El Houate et al, 2007], and Asn110Lys [Bogatcheva et al, 2003]. However, it has to be considered that many of these mutations are located in the C-peptide that is normally excised during processing of the preprohormone, and molecular modeling and comparative analyses of protein sequences in most cases revealed the importance of the mutated amino acids.…”