Cabrera-López Cristina, Bullich Gemma, Martí Teresa, Català Violeta, Ballarín Jose, Bissler John J, Harris Peter C, Ars Elisabet, Torra Roser
Inherited Kidney Diseases, Nephrology Department, Fundació Puigvert, Instituto de Investigaciones Biomédicas Sant Pau (IIB-Sant Pau), Universitat Autònoma de Barcelona, REDinREN, Instituto de Investigación Carlos III, Cartagena 340-350, 08025, Barcelona, Spain.
Molecular Biology Laboratory, Fundació Puigvert, Instituto de Investigaciones Biomédicas Sant Pau (IIB-Sant Pau), Universitat Autònoma de Barcelona, REDinREN, Instituto de Investigación Carlos III, Barcelona, Spain.
BMC Med Genet. 2015 Jun 17;16:39. doi: 10.1186/s12881-015-0185-y.
Mutations in TSC1 or TSC2 cause the tuberous sclerosis complex (TSC), while mutations in PKD1 or PKD2 cause autosomal dominant polycystic kidney disease (ADPKD). PKD1 lays immediately adjacent to TSC2 and deletions involving both genes, the PKD1/TSC2 contiguous gene syndrome (CGS), are characterized by severe ADPKD, plus TSC. mTOR inhibitors have proven effective in reducing angiomyolipoma (AML) in TSC and total kidney volume in ADPKD but without a positive effect on renal function.
We describe a patient with independent truncating PKD1 and TSC2 mutations who has the expected phenotype for both diseases independently instead of the severe one described in PKD1/TSC2-CGS. Treatment with mTOR inhibitors reduced the AML and kidney volume for 2 years but thereafter they resumed growth; no positive effect on renal function was seen throughout. This is the first case addressing the response to mTOR treatment when independent truncating mutations in PKD1 and TSC2 are present.
This case reveals that although PKD1 and TSC2 are adjacent genes and there is likely cross-talk between the PKD1 and TSC2 signalling pathways regulating mTOR, having independent TSC2 and PKD1 mutations can give rise to a milder kidney phenotype than is typical in PKD1/TSC2-CGS cases. A short-term beneficial effect of mTOR inhibition on AML and total kidney volume was not reflected in improved renal function.
TSC1或TSC2基因的突变会导致结节性硬化症（TSC），而PKD1或PKD2基因的突变会导致常染色体显性多囊肾病（ADPKD）。PKD1紧邻TSC2，涉及这两个基因的缺失，即PKD1/TSC2相邻基因综合征（CGS），其特征为严重的ADPKD合并TSC。mTOR抑制剂已被证明可有效减少TSC患者的血管平滑肌脂肪瘤（AML）以及ADPKD患者的总肾体积，但对肾功能无积极影响。
我们描述了一名患有独立截断性PKD1和TSC2突变的患者，其分别呈现出两种疾病预期的表型，而非PKD1/TSC2-CGS中所描述的严重表型。mTOR抑制剂治疗使AML和肾体积缩小了2年，但此后又重新增大；整个过程中对肾功能均未见积极影响。这是首例针对存在独立截断性PKD1和TSC2突变时mTOR治疗反应的病例。
该病例表明，尽管PKD1和TSC2是相邻基因，且在调节mTOR的PKD1和TSC信号通路之间可能存在相互作用，但存在独立的TSC2和PKD1突变时，所产生的肾脏表型可能比典型的PKD1/TSC2-CGS病例更为轻微。mTOR抑制对AML和总肾体积的短期有益作用并未体现在肾功能的改善上。
