Peral B, Ong A C, San Millán J L, Gamble V, Rees L, Harris P C
MRC Molecular Haematology Unit, Institute of Molecular Medicine, John Radcliffe Hospital, Oxford, UK.
Hum Mol Genet. 1996 Apr;5(4):539-42. doi: 10.1093/hmg/5.4.539.
Autosomal dominant polycystic kidney disease (ADPKD) is the most common single gene disorder resulting in renal failure. It is generally an adult onset disease, but rarely, cases of severe childhood polycystic disease arise in ADPKD families. The clear clinical anticipation in these pedigrees has led to the suggestion that the mutation may be an unstable trinucleotide repeat. We have now identified a nonsense mutation, Tyr3818Stop, in one such family (P117) within the major ADPKD gene, polycystic kidney disease 1 (PKD1). The mutation is shown to be a de novo change in the father, and of grandpaternal origin. PKD1 manifests as typical adult onset disease in the father, but is seen as severe disease, detected as enlarged polycystic kidneys in utero, in one of a pair of dizygotic twins; the other twin has the mutation but no evidence of cysts, consistent with an adult onset disease course. The finding of the same stable mutation associated with very different disease severity in this family indicates that phenotypic variation in PKD1 is not due to a dynamic mutation. It seems most likely that a small number of modifying factors may radically affect the course of disease in PKD1; identification of such factors will have important prognostic implications in this disorder.
常染色体显性多囊肾病（ADPKD）是导致肾衰竭的最常见单基因疾病。它通常是一种成人发病的疾病，但在ADPKD家族中，严重的儿童多囊病病例很少出现。这些家系中明显的临床遗传早现现象提示该突变可能是一种不稳定的三核苷酸重复序列。我们现已在一个这样的家系（P117）中，于主要的ADPKD基因——多囊肾病1（PKD1）中鉴定出一个无义突变，即Tyr3818Stop。该突变在父亲中显示为新发突变，且源自祖父。PKD1在父亲身上表现为典型的成人发病疾病，但在一对异卵双胞胎中的一个胎儿期就被检测出多囊肾肿大，表现为严重疾病；另一个双胞胎有该突变，但无囊肿迹象，符合成人发病的病程。在这个家族中发现相同的稳定突变却伴有截然不同的疾病严重程度，这表明PKD1的表型变异并非由动态突变所致。很可能是少数修饰因子可能从根本上影响PKD1的疾病进程；识别这些因子将对这种疾病具有重要的预后意义。
