title: Insight into response to mTOR inhibition when PKD1 and TSC2 are mutated.
abstract: 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.
  
  
  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.
authors.affiliation: 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. cristinacabrera79@hotmail.com.
authors.forename: Cristina
authors.initials: C
authors.lastname: Cabrera-López
authors.affiliation: 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. gbullich@fundacio-puigvert.es.
authors.forename: Gemma
authors.initials: G
authors.lastname: Bullich
authors.affiliation: Radiology Department, Fundació Puigvert, Barcelona, Spain. tmarti@fundacio-puigvert.es.
authors.forename: Teresa
authors.initials: T
authors.lastname: Martí
authors.affiliation: Radiology Department, Fundació Puigvert, Barcelona, Spain. vcatala@fundacio-puigvert.es.
authors.forename: Violeta
authors.initials: V
authors.lastname: Català
authors.affiliation: Nephrology Department, Fundació Puigvert, Instituto de Investigaciones Biomédicas Sant Pau (IIB-Sant Pau), Universitat Autònoma de Barcelona, REDinREN, Instituto de Investigación Carlos III, Barcelona, Spain. jballarin@fundacio-puigvert.es.
authors.forename: Jose
authors.initials: J
authors.lastname: Ballarín
authors.affiliation: Pediatric Nephrology Department, Le Bonheur Children's Hospital, Memphis, TN, USA. jbissler@uthsc.edu.
authors.forename: John J
authors.initials: JJ
authors.lastname: Bissler
authors.affiliation: Department of Biochemistry and Molecular Biology, Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, USA. harris.peter@mayo.edu.
authors.forename: Peter C
authors.initials: PC
authors.lastname: Harris
authors.affiliation: 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. ears@fundacio-puigvert.es.
authors.forename: Elisabet
authors.initials: E
authors.lastname: Ars
authors.affiliation: 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. rtorra@fundacio-puigvert.es.
authors.forename: Roser
authors.initials: R
authors.lastname: Torra
mesh_terms: D000328:Adult; D000368:Aged; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D050396:TRPP Cation Channels / Q000235:genetics*; D016896:Treatment Outcome; D014402:Tuberous Sclerosis / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000235:genetics*
chemical_list: D047428:Protein Kinase Inhibitors; D058570:TOR Serine-Threonine Kinases; D050396:TRPP Cation Channels; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; C000624653:TSC2 protein, human