Insight into response to mTOR inhibition when PKD1 and TSC2 are mutated

Abstract

BackgroundMutations 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 resultsWe 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.ConclusionsThis 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.

Two cases of TSC2/PKD1 contiguous gene deletion syndrome

“…Instead, mTOR inhibitor was effective in reducing angiomyolipoma volume in patients with TSC [18]. In patients with TSC2/PKD1 CGDS as well, mTOR inhibitor was not effective for improving renal function, but produced the satisfactory effect of renal angiomyolipoma size reduction [9]. Renal involvement was shown in our patients even at the age of 12 months.…”

“…The mutations in TSC2 and PKD1 seem to produce a truncated tuberin which activates guanosine triphosphatase (GTPase), leading to a reduction in mammalian target of rapamycin (mTOR) stimulation. The disruption of these genes was expected to result in cyst enlargement through mTOR activation [9]. In recent studies, however, mTOR inhibitors were not successful in treating the renal involvement of TSC and ADPKD.…”

“…TSC2/PKD1 CGDS can occur due to the adjacent location of the TSC2 and PKD1 genes. More cases have been reported in TSC patients with enlarged polycystic kidneys [7][8][9][10][11][12][13][14]. Although 5% of patients with TSC have TSC2/PKD1 CGDS, there have been no report of patients with TSC2/PKD1 CGDS in the Korean population.…”

Thyroid nodules on chest CT of patients with tuberous sclerosis complex

“…Two patients had the TSC2/PKD1 CGS and presented with normal thyroid glands. Patients with the TSC2/PKD1 CGS have more severe renal disease [Brook‐Carter et al, ; Cabrera‐López et al, ] and cysts in the thyroid gland [Ul Haque and Moatasim, ]. Yet our findings do not demonstrate a higher incidence of thyroid affection in such patients.…”

Familial genetic tuberous sclerosis complex associated with bilateral giant renal angiomyolipoma: A case report

“…Tuberous sclerosis complex (TSC) is an autosomal dominant disease, which typically causes benign tumors to develop in the brain and other vital organs, including the kidney, skin and liver ( 1 , 2 ). Global statistics from previous studies, performed in 2000 and 2011, revealed that 1/6,000-10,000 people are born with TSC and there are 2,000,000 people with TSC ( 3 , 4 ) TSC is a genetic disease, with 33% of patients with TSC having inherited the disease, and 66% of patients with TSC having developed the disease due to a gene mutation ( 5 ).…”