The Sprott Centre for Stem Cell Research, Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.
Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada.
J Am Soc Nephrol. 2023 Jul 1;34(7):1135-1149. doi: 10.1681/ASN.0000000000000146. Epub 2023 Apr 15.
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.
结节性硬化症（TSC）肾脏病变的表型多样性是一个谜。尽管其具有明确的单基因病因，但对病变发病机制的认识仍不完整。在这篇综述中，我们探讨了一个问题：TSC 肾脏病变是如何产生的？我们根据突变时间和细胞起源来评估文献研究结果。通过发育的角度，我们整合了临床研究、人类标本和遗传动物模型的关键结果。我们还回顾了新兴类器官和单细胞测序技术获得的新见解。我们提出了一种新的发病机制模型，该模型假设存在一种表型连续体，即病变是由发育过程中随机发生的二次打击事件导致突变产生的。该模型可以作为一个概念框架，用于检验 TSC 病变发病机制的假说，不仅在肾脏，而且在其他受影响的组织中也是如此。
