DENTS DISEASE, A RENAL FANCONI SYNDROME WITH NEPHROCALCINOSIS AND KIDNEY-STONES, IS ASSOCIATED WITH A MICRODELETION INVOLVING DXS255 AND MAPS TO XP11.22

Dent's disease is a familial proximal renal tubular disorder which is associated with low molecular weight proteinuria, hypercalciuria, neph rocalcinosis, kidney stones and renal failure. The mode of inheritance and the primary defect for this disorder are unknown. An analysis of 5 unrelated British families revealed a greater disease severity in ma les and an absence of male to male transmission. This suggested an X-l inked inheritance and we investigated this further by linkage studies in 33 members (12 affected, 21 unaffected) from two 3-generation famil ies. Twenty X-linked polymorphic markers were used and linkage was est ablished with the Xp11 loci ARAFl, DXS426, DXS255 and DXS988 with peak LOD scores and recombination fractions (theta) of 5.42 (theta = 0.000 ), 3.61 (theta = 0.000), 5.48 (theta = 0.000) and 4.25 (theta = 0.045) respectively. In addition, DXS255 revealed a microdeletion in the aff ected members of one family, thereby further localising Dent's disease to Xp11.22. Combined multilocus linkage analysis and deletion mapping studies defined the locus order Xpter-MAOB-(ARAFl, DXS426)-SYP-TFE3-( DXS255, DENT'S)-DXS988-Xcen, thereby mapping the microdeletion associa ted with Dent's disease to a 4 centiMorgan interval flanked by TFE3 an d DXS988. Thus, Dent's disease is an X-linked disorder which is associ ated with a microdeletion of Xp11.22, and a further characterisation o f this gene will help to elucidate the factors controlling proximal re nal tubular function and the development of kidney stones.