PKD1 and Associated Diseases
Creative Biolabs is a reputable innovative biotechnology company that has been at the forefront of gene therapy for decades. After decades of expansion and accumulation, Creative Biolabs has built an advanced technology platform. We specialize in customizing gene therapy services according to your needs. We are always willing to share the knowledge background related to gene therapy, here we give a brief introduction to polycystin 1, transient receptor potential channel interacting (PKD1) gene.
Normal Function of PKD1
PKD1 is a protein-coding gene that encodes polycystin 1 (PC1), a member of the polycystin family. PC1 is an integral membrane protein consisting of an N-terminal extracellular domain, multiple transmembrane domains as well as a cytoplasmic C-tail. PC1 spans the cell membrane of kidney cells, so one end of the protein resides inside the cell and the other end is on the extracellular surface. This specialized localization enables it to interact with other molecules including carbohydrates, proteins, and lipids outside the cell and to act as a signal receiver that helps the cell respond to the environment. When the molecule binds to PC1 on the cell surface, the protein interacts with polycystin-2 (PC2), which induces a variety of intracellular chemical reactions. PC1 and PC2 may work together to regulate cell proliferation, cell migration, and cell-cell interactions. Furthermore, PC1 is a calcium-permeable cation channel and a crucial regulator of intracellular calcium homeostasis.
PKD1 and Autosomal Dominant Polycystic Didney Disease Type 1 (ADPKD1)
PKD1 is critical for tubular development, and mutations in this gene are strongly associated with ADPKD1. ADPKD1 is primarily characterized by fluid-filled cysts that replace normal kidney tissue and lead to end-stage renal failure. Mutations in the PKD1 gene mainly involve insertions or deletions of DNA base pairs as well as base pair changes. Most PKD1 mutations can result in abnormal, non-functional PC1 protein. Abnormal PC1 may disrupt the signaling function of proteins within cells and in primary cilia, which may eventually lead to abnormal growth and division of cells in the inner wall of the kidney tubules and massive cyst growth.
Fig.1 Localisation and processing of PC1/PC2 complexes in polarised epithelial cells. (Ong, 2017)
ADPKD1 Related Pathways
Similar to PKD1, the tuberous sclerosis complex 2 (TSC2) gene is located on chromosome 16, and its protein product is tuberin. Tuberin is a key regulator of the activity of the mammalian targets of rapamycin (mTOR). PC1 retains tuberin protein on the plasma membrane by interacting with it to inhibit the mTOR pathway. Thus, the mTOR pathway is activated in cases of ADPKD due to abnormal PC1. Furthermore, in the epithelial cells lining ADPKD cysts, mTOR kinase activity is increased, therefore, the administration of mTOR inhibitors is considered a promising therapeutic approach for ADPKD.
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Reference
- Ong, A.C. Making sense of polycystic kidney disease. The Lancet. 2017, 389(10081): 1780-1782.
