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

Area of Science:

• Genetics
• Molecular Biology
• Nephrology

Background:

• Mutations in TSC1/TSC2 cause tuberous sclerosis complex (TSC); mutations in PKD1/PKD2 cause autosomal dominant polycystic kidney disease (ADPKD).
• PKD1 and TSC2 genes are adjacent, and deletions involving both cause PKD1/TSC2 contiguous gene syndrome (CGS) with severe phenotypes.
• mTOR inhibitors are used for TSC-related angiomyolipoma (AML) and ADPKD kidney volume, but their effect on renal function is limited.

Observation:

• A patient with independent truncating mutations in both PKD1 and TSC2 presented with phenotypes of both diseases, but milder than typical CGS.
• Treatment with mTOR inhibitors initially reduced AML and kidney volume over two years.
• After two years, AML and kidney volume began to grow again, with no improvement in renal function observed.

Findings:

• Independent PKD1 and TSC2 mutations result in a less severe kidney phenotype compared to PKD1/TSC2-CGS.
• mTOR inhibition provides a temporary reduction in AML and kidney volume in patients with independent PKD1 and TSC2 mutations.
• mTOR inhibitors do not improve renal function in this patient cohort, despite short-term effects on disease burden.

Implications:

• Cross-talk between PKD1 and TSC2 signaling pathways regulating mTOR exists, influencing disease severity.
• The genetic interaction between PKD1 and TSC2 impacts disease presentation and response to mTOR inhibitors.
• Further research is needed to understand the long-term efficacy and mechanisms of mTOR inhibitors in TSC and ADPKD, especially concerning renal function preservation.