Polycystin 1 (PKD1) mRNA 5' untranslated region (UTR) upstream open reading frame (uORF) (PKD1 mRNA 5'UTR uORF)

The Polycystin 1 (PKD1) mRNA 5' untranslated region (UTR) contains upstream open reading frames (uORFs) that act as potent inhibitors of the translation of the main PKD1 protein (Lakhia et al., 2022, JASN). In patients with Autosomal Dominant Polycystic Kidney Disease (ADPKD), mutations often result in a reduction of PKD1 protein levels below a critical threshold, leading to the formation of fluid-filled cysts in the kidneys (NIH, 2023). The uORFs in the 5'UTR of the remaining healthy PKD1 allele further suppress protein production, exacerbating the deficiency (Ramalingam et al., 2021, Nature Communications). Therapeutic intervention involves the use of antisense oligonucleotides (ASOs) designed to bind to and block these uORFs, which prevents the ribosome from initiating translation at the inhibitory upstream sites and instead promotes translation of the primary PKD1 coding sequence (Lakhia et al., 2022, JASN). This strategy aims to boost endogenous PKD1 levels to therapeutic levels, potentially slowing disease progression and reducing cyst burden. Current development focuses on optimizing the delivery of these RNA-based therapies to the renal tubular epithelium and ensuring long-term safety (PubMed, 2022).

Other names

PKD1 uORFPolycystin-1 5'UTR uORFUpstream open reading frame of Polycystin 1

Steric blocking of the uORF start codon to enhance translation of the primary open reading frame (Lakhia et al., 2022, JASN).