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

Malformations of the kidney and lower urinary tract are common causes of chronic renal failure in infants and young children, but little is known about the molecular pathogenesis of these disorders. In animal experiments, the main causes of malformation are mutations, chemical and pharmaceutical teratogens, obstruction of fetal urinary flow, and alterations of maternal nutrition. The focus of this review is to consider how mutations and other alterations of gene expression during development cause human urinary tract malformations. Some of these disorders are associated with congenital anomalies in multiple organ systems, and two such syndromes are considered in detail: first, the renal-coloboma syndrome, in which mutations of the PAX2 transcription factor cause partial failure of urinary tract growth; second, Kallmann's syndrome, in which mutations of a cell-signaling molecule are associated with the absence of the urinary tract. In patients seen by nephrologists and urologists, however, most urinary tract malformations occur in isolation, and in some of these individuals, a genetic pathogenesis is strongly suggested by a positive family history and genetic linkage studies. One common example is primary vesicoureteric reflux. Furthermore, sporadic malformations have been shown to be associated with polymorphisms of genes expressed during construction of the urinary tract. In the long term, an understanding of the genetic aspects of human urinary tract malformations will help to unravel the pathogenesis of these disorders and may facilitate the design of genetic screening tests with a view to early diagnosis.