CHROMOSOME-1 LOCALIZATION OF A GENE FOR AUTOSOMAL-DOMINANT MEDULLARY CYSTIC KIDNEY-DISEASE (ADMCKD)

There is a group of inherited cystic nephropathies that are characteri zed by juvenile onset recessive inheritance (familial juvenile nephron ophthisis, FJN) or by adult onset dominant inheritance (medullary cyst ic disease, MCD) and share similar clinico-pathological presentation t o the extent that they are usually grouped together under the term FJN /MCD complex. The main symptoms consist of renal cyst formation in the medulla or the corticomedullary junction and salt wasting. Although e arlier reports had suggested that one single gene may be responsible f or this pathology, recent reports have shown that the FJN complex itse lf comprises a genetically heterogeneous group. Here we are presenting two large Cypriot families that segregate autosomal dominant medullar y cystic kidney disease (ADMCKD) with hyperuricemia and gout and with very late age of onset (mean 62.2 and 51.5 years). We performed DNA li nkage mapping using highly polymorphic microsatellite markers and foun d linkage to marker locus D1S1595 at 1q21 with a two-point lod score o f 6.45 at Theta = 0.00. Analysis of haplotypes and of critical recombi nants enabled confinement of the disease locus within an similar to 8 cM region between marker loci D1S498 and D1S2125. FISH mapping with a large P1 clone confirmed the physical localization within 1q21. The tw o families share the same disease haplotype, thus suggesting their rel ationship through a common ancestor and the possible existence of a si ngle ADMCKD-causing mutation within these families. To our knowledge t his is the first genetic locus identified to cause FJN/MCD pathology o f the dominant adult type.