Genetic analysis of the INSL3 gene in patients with maldescent of the testis

Objective: Testicular maldescent is important because it is a common congen ital disorder that is associated with an increased risk of infertility and testicular cancer. Murine studies indicate that testicular maldescent can r esult from disruption of insulin-like factor 3 (INSL3) activity and that it may be more severe when there is concurrent undermasculinisation. Therefor e, the INSL3 gene was screened for mutations and polymorphisms that may con tribute to testicular maldescent in patients with undermasculinisation as w ell as those with isolated testicular maldescent. Methods and Results: The patient groups consisted of individuals with isolated testicular maldescent (n = 28) and patients with undermasculinised genitalia and intra-abdominal (n = 24) or inguinal gonads (n = 33). The three control groups were: norma l males (n = 15), males with undermasculinised genitalia and scrotal gonads (n = 29) and females (n = 82). SSCP/HA mutation screening detected eight v ariants, five of which were predicted to alter the protein sequence (A-1G, V19L. P25S, A36T. R78H). Three of the amino acid changes (A-1G. V19L, R78H) each occurred in a single control sample and one was identified in a male with undermasculinised genitalia and intraabdominal testes (P25S). The A36T amino acid polymorphism was found in both patient and control groups at a similar frequency. Conclusions: The evidence suggests that INSL 3 mutations and polymorphisms are not a major cause of testicular maldescent with or w ithout associated undermasculinisation.