Hypospadias : Analysis of a complex genetic disorder

BACKGROUND: Hypospadias is a common inborn error of the male urethra that involves an abnormally placed urethral opening. Its complex etiology is largely elusive to date. Twin and familial studies highlight a genetic background in hypospadias. Environmental factors have also been identified, particularly the exposure to endocrine disrupters. For most of the cases, pedigree analyses indicate a heterogeneous, complex pattern of inheritance, with several genetic and environmental factors interacting, yielding high heritability indices. Hypospadias is therefore said to be a complex genetic disorder. HYPOTHESIS: As an inborn error of development, hypospadias may be induced by disturbances in the pathways of urethral development, which comprise genetic programming, cell differentiation, hormonal signaling, enzyme activity, and tissue remodeling; and follows an orderly sequence. We proposed that gene variants in FGF8, FGF10, FGFR2 and BMP7, important genes in the early urethral development; in FKBP52, an androgen receptor cochaperone; in the estrogen receptor (ESR) genes 1 and 2; and ATF3, an estrogen responsive gene; may influence the risk to hypospadias. STRATEGY: Using a candidate gene strategy, we performed comprehensive analysis of these genes in DNA from boys with hypospadias and controls, including sequence analysis, genotyping and association studies; and complementary expression analysis in human tissues. RESULTS: Our results indicate that gene variants in the sequence of FGF8, FGFR2, two androgen‐regulated developmental genes; and of ESR2 and ATF3, two estrogen related genes, are associated with hypospadias. We have shown that the last is expressed in the human developing male urethra. DISCUSSION: The molecular mechanisms involved in the development of external genitalia during fetal life seem to depend on a complex balance between early morphogenetic cell‐cell interactions; and between sex steroid hormones. These balances can be disturbed by the exposure to environmental endocrine disruptors. Ethnical differences in the response to such exposures denote that genetic factors also play an important role. The involvement of sequence variants in FGFR2, FGF8, ESR2 and ATF3, hormonal responsive genes, in hypospadias is reported in this thesis, increasing the understanding on the complex etiology of hypospadias. Further genetic analysis and gene‐environment studies are encouraged