A molecular and genetic view of human renal and urinary tract malformations

Malformations of the kidney and lower urinary tract are common causes of ch ronic renal failure in infants and young children, but little is known abou t the molecular pathogenesis of these disorders. In animal experiments, the main causes of malformation are mutations, chemical and pharmaceutical ter atogens, obstruction of fetal urinary flow, and alterations of maternal nut rition. The focus of this review is to consider how mutations and other alt erations of gene expression during development cause human urinary tract ma lformations. Some of these disorders are associated with congenital anomali es in multiple organ systems, and two such syndromes are considered in deta il: first. the renal-coloboma syndrome, in which mutations of the PAX2 tran scription factor cause partial failure of urinary tract growth; second, Kal lmann's syndrome, in which mutations of a cell-signaling molecule are assoc iated with the absence of the urinary tract. In patients seen by nephrologi sts and urologists, however, most urinary tract malformations occur in isol ation, and in some of these individuals, a genetic pathogenesis is strongly suggested by a positive family history and genetic linkage studies. One co mmon example is primary vesicoureteric reflux. Furthermore, sporadic malfor mations have been shown to be associated with polymorphisms of genes expres sed during construction of the urinary tract. In the long term, an understa nding of the genetic aspects of human urinary tract malformations will help to unravel the pathogenesis of these disorders and may facilitate the desi gn of genetic screening tests with a view to early diagnosis.