Tuberous Sclerosis Complex Kidney Lesion Pathogenesis: A Developmental Perspective

The phenotypic diversity of tuberous sclerosis complex (TSC) kidney pathology is enigmatic. Despite a well-established monogenic etiology, an incomplete understanding of lesion pathogenesis persists. In this review, we explore the question: How do TSC kidney lesions arise? We appraise literature findings in the context of mutational timing and cell-of-origin. Through a developmental lens, we integrate the critical results from clinical studies, human specimens, and genetic animal models. We also review novel insights gleaned from emerging organoid and single-cell sequencing technologies. We present a new model of pathogenesis which posits a phenotypic continuum, whereby lesions arise by mutagenesis during development from variably timed second-hit events. This model can serve as a conceptual framework for testing hypotheses of TSC lesion pathogenesis, both in the kidney and in other affected tissues.

Automated summary

This review explores the question of how TSC kidney lesions arise, integrating findings from clinical studies, human specimens, and genetic animal models. It presents a new model of pathogenesis suggesting that lesions arise from second-hit events during development. This model can serve as a conceptual framework for investigating TSC lesion pathogenesis in various tissues.