INSL3 – Cryptorchidism

The insulin-like 3 (INSL3) hormone is secreted by testicular Leydig cells during fetal development and binds the G protein-coupled receptor RXFP2 to mediate the transabdominal phase of testicular descent. In murine models, genetic ablation of Insl3 or Rxfp2 results in bilateral intra-abdominal cryptorchidism, implicating this ligand–receptor pair in gubernacular development and hormonally driven descent.

Autosomal recessive INSL3 variants have been reported in human cryptorchidism cohorts. In 600 newborns with cryptorchidism, two heterozygous INSL3 mutations were identified in unilateral cases and absent in 300 controls (PMID:19416190). In 87 ex-cryptorchid men, three missense variants (c.305G>A (p.Arg102His), c.278C>T (p.Pro93Leu), c.304C>T (p.Arg102Cys)) were found in four patients, maternally inherited (PMID:12970298). A larger series of 135 patients detected six additional INSL3 variants in six subjects (7.4% prevalence) with preserved endocrine function (PMID:15353080).

Screening of 967 individuals with testicular dysgenesis features uncovered six INSL3 mutations in 18 cases (1.9%) and none in 450 controls; functional cAMP assays for p.Arg4His and p.Trp69Arg showed normal receptor activation, suggesting variable impact on signaling (PMID:16687567).

A recent exome analysis of 2412 men from the MERGE cohort identified a homozygous INSL3 frameshift c.143dup (p.Arg50ProfsTer16) in patients with bilateral cryptorchidism and infertility. Affected individuals lacked Leydig INSL3 staining and had undetectable serum INSL3, confirming an autosomal recessive loss-of-function mechanism (PMID:37208861).

Functional concordance is supported by mouse Insl3 and Rxfp2 knockouts that phenocopy human cryptorchidism, and in vitro studies demonstrate that INSL3 stimulates cAMP production and cell proliferation in gubernacular and Leydig cells via RXFP2 (PMID:19416188). Population studies in Japanese cohorts have not implicated common INSL3 polymorphisms in sporadic cryptorchidism risk (PMID:11380919).

Collectively, multiple independent cohorts and animal models establish Moderate clinical validity for INSL3 in autosomal recessive cryptorchidism, with genetic and functional data supporting a loss-of-function mechanism. Key take-home: INSL3 genetic testing should be considered in familial or bilateral cryptorchidism to guide diagnosis and management.

References

• Annals of the New York Academy of Sciences • 2009 • Mutations in INSL3 and RXFP2 genes in cryptorchid boys. PMID:19416190
• The Journal of clinical endocrinology and metabolism • 2003 • The INSL3-LGR8/GREAT ligand-receptor pair in human cryptorchidism. PMID:12970298
• Reproductive biomedicine online • 2004 • Role of INSL3 and LGR8 in cryptorchidism and testicular functions. PMID:15353080
• Molecular human reproduction • 2006 • Insulin-like factor 3 gene mutations in testicular dysgenesis syndrome: clinical and functional characterization. PMID:16687567
• Annals of the New York Academy of Sciences • 2009 • INSL3/RXFP2 signaling in testicular descent. PMID:19416188
• Pediatrics international : official journal of the Japan Pediatric Society • 2001 • Ala/Thr60 variant of the Leydig insulin-like hormone is not associated with cryptorchidism in the Japanese population. PMID:11380919
• Human reproduction (Oxford, England) • 2023 • Bi-allelic variants in INSL3 and RXFP2 cause bilateral cryptorchidism and male infertility. PMID:37208861

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