Clinical and molecular heterogeneity of juvenile nephronophthisis in Italy: Insights from molecular screening

Autosomal recessive nephronophthisis (NPH) is a renal disorder histological ly characterized by tubulointerstitial lesions that are, in some cases, ass ociated with extrarenal manifestations such as tapeto-retinal degeneration or liver fibrosis, The disease is usually pauci-symptomatic in an early pha se but invariably evolves to end-stage renal failure in childhood or early adulthood. The recent discovery of the NPHP1 gene (nephrocystin) has prompt ed research into putative genotype-phenotype correlations. We screened a po pulation of 68 Italian children (10 multiplex families, 47 sporadic cases) with a clinical and histopathologic picture of NPH and found a large homozy gous deletion at 2q13 involving nephrocystin in 30 cases, and heterozygous deletion associated with new point mutations at exons 15 (Tyr518Ter) and 17 (Arg585Ter) of the gene in two other cases. The remaining 36 children had no apparent molecular defects of nephrocystin. In spite of this genetic het erogeneity, the two groups, with and without detectable molecular defects o f nephrocystin, showed similar renal defects and comparable cumulative surv ival considering the start of dialysis as an end-point, The unique differen ce observed was a less frequent requirement of dialysis in NPH1 patients wi th pure renal form. Finally, tapeto-retinal degeneration was associated wit h renal lesions in seven cases presenting deletion of the nephrocystin gene and in five sporadic cases without molecular defects. These data show that a molecular defect of nephrocystin is involved in approximately 50% of pat ients with NPH, and another 50% require further molecular characterization. Research therefore should now be aimed at characterizing a new locus. In s pite of the molecular heterogeneity, NPH in children presents similar renal and extrarenal manifestations, thus suggesting the involvement of common p athological routes. (C) 2000 by the National Kidney Foundation, Inc.