Insight into response to mTOR inhibition when PKD1 and TSC2 are mutated
Por:
Cabrera-Lopez, C, Bullich, G, Marti, T, Catala, V, Ballarin, J, Bissler, JJ, Harris, PC, Ars, E, Torra, R
Publicada:
17 jun 2015
Resumen:
Background: 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.
Methods and results: 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.
Conclusions: 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.
Filiaciones:
Cabrera-Lopez, C:
Univ Autonoma Barcelona, Inst Invest Carlos III, Inst Invest Biomed St Pau IIB St Pau, Inherited Kidney Dis,Fdn Puigvert,REDinREN,Dept N, Barcelona 08025, Spain
Bullich, G:
Univ Autonoma Barcelona, Inst Invest Carlos III, Inst Invest Biomed St Pau IIB St Pau, Mol Biol Lab,Fdn Puigvert,REDinREN, Barcelona 08025, Spain
Marti, T:
Fundacio Puigvert, Dept Radiol, Barcelona, Spain
Catala, V:
Fundacio Puigvert, Dept Radiol, Barcelona, Spain
Ballarin, J:
Univ Autonoma Barcelona, Inst Invest Carlos III, Inst Invest Biomed St Pau IIB St Pau, Dept Nephrol,Fundacio Puigvert,REDinREN, Barcelona 08025, Spain
Bissler, JJ:
Le Bonheur Childrens Hosp, Pediat Nephrol Dept, Memphis, TN USA
Harris, PC:
Mayo Clin, Div Nephrol & Hypertens, Dept Biochem & Mol Biol, Rochester, MN USA
Ars, E:
Univ Autonoma Barcelona, Inst Invest Carlos III, Inst Invest Biomed St Pau IIB St Pau, Mol Biol Lab,Fdn Puigvert,REDinREN, Barcelona 08025, Spain
Torra, R:
Univ Autonoma Barcelona, Inst Invest Carlos III, Inst Invest Biomed St Pau IIB St Pau, Inherited Kidney Dis,Fdn Puigvert,REDinREN,Dept N, Barcelona 08025, Spain
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