Christodoulou K, Tsingis M, Stavrou C, Eleftheriou A, Papapavlou P, Patsalis P C, Ioannou P, Pierides A, Constantinou Deltas C
Department of Molecular Genetics, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus.
Hum Mol Genet. 1998 May;7(5):905-11. doi: 10.1093/hmg/7.5.905.
There is a group of inherited cystic nephropathies that are characterized by juvenile onset recessive inheritance (familial juvenile nephronophthisis, FJN) or by adult onset dominant inheritance (medullary cystic disease, MCD) and share similar clinico-pathological presentation to 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 earlier reports had suggested that one single gene may be responsible for this pathology, recent reports have shown that the FJN complex itself comprises a genetically heterogeneous group. Here we are presenting two large Cypriot families that segregate autosomal dominant medullary 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 linkage mapping using highly polymorphic microsatellite markers and found linkage to marker locus D1S1595 at 1q21 with a two-point lod score of 6.45 at Theta = 0.00. Analysis of haplotypes and of critical recombinants enabled confinement of the disease locus within an approximately 8 cM region between marker loci D1S498 and D1S2125. FISH mapping with a large P1 clone confirmed the physical localization within 1q21. The two families share the same disease haplotype, thus suggesting their relationship through a common ancestor and the possible existence of a single ADMCKD-causing mutation within these families. To our knowledge this is the first genetic locus identified to cause FJN/MCD pathology of the dominant adult type.
有一组遗传性囊性肾病，其特征为青少年发病的隐性遗传（家族性青少年肾单位肾痨，FJN）或成人发病的显性遗传（髓质囊性疾病，MCD），并且具有相似的临床病理表现，以至于它们通常被归为FJN/MCD综合征。主要症状包括髓质或皮质髓质交界处的肾囊肿形成以及失盐。尽管早期报告曾表明单个基因可能是这种病理状况的病因，但最近的报告显示FJN综合征本身包含一组基因异质性疾病。在此，我们呈现两个大型塞浦路斯家族，它们患有伴有高尿酸血症和痛风且发病年龄很晚（平均62.2岁和51.5岁）的常染色体显性髓质囊性肾病（ADMCKD）。我们使用高度多态性的微卫星标记进行了DNA连锁图谱分析，发现与位于1q21的标记位点D1S1595连锁，在Theta = 0.00时两点连锁lod值为6.45。单倍型分析和关键重组体分析将疾病位点限定在标记位点D1S498和D1S2125之间约8 cM的区域内。用一个大型P1克隆进行荧光原位杂交图谱分析证实了其在1q21内的物理定位。这两个家族共享相同的疾病单倍型，因此表明它们通过共同祖先存在关联，并且这些家族中可能存在一个导致ADMCKD的单一突变。据我们所知，这是首次鉴定出导致成人显性类型FJN/MCD病理状况的基因位点。
