A no-nonsense approach to hereditary kidney disease
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REVIEW
A no-nonsense approach to hereditary kidney disease Fatima Tokhmafshan 1 & Kyle Dickinson 1,2 & Murielle M. Akpa 1 & Emma Brasell 3 & Pedro Huertas 4 & Paul R. Goodyer 1,2,3,5 Received: 18 March 2019 / Revised: 5 July 2019 / Accepted: 7 October 2019 # IPNA 2019
Abstract The advent of a new class of aminoglycosides with increased translational readthrough of nonsense mutations and reduced toxicity offers a new therapeutic strategy for a subset of patients with hereditary kidney disease. The renal uptake and retention of aminoglycosides at a high intracellular concentration makes the kidney an ideal target for this approach. In this review, we explore the potential of aminoglycoside readthrough therapy in a number of hereditary kidney diseases and discuss the therapeutic window of opportunity for subclasses of each disease, when caused by nonsense mutations. Keywords Nonsense mutation . Premature STOP codon . Hereditary kidney disease . Aminoglycosides . Translational readthrough
Introduction Nonsense mutations in kidney disease: therapeutic potential of aminoglycosides Ten percent of all genetic diseases are caused by nonsense mutations, which generate premature termination codons (UAA, UAG, or UGA) that lack cognate tRNAs. As a result, mRNA translation stops prematurely, releasing a truncated polypeptide and activating rapid degradation of the transcript through nonsense-mediated mRNA decay (NMD) [1, 2]. Hildebrandt estimates that there are over 50 monogenic kidney diseases; NMD are involved in a subgroup of each [3, 4]. In this context, monogenic refers to a disease phenotype that is largely attributable to a single genetic locus, implying that correction of the mutant locus should correct the disease phenotype. With the
* Paul R. Goodyer [email protected] 1
Research Institute of the McGill University Health Center, 1001 Décarie Boulevard, EM1.2232, Montreal, QC H4A 3J1, Canada
2
Department of Experimental Medicine, McGill University, Montreal, Canada
3
Department of Human Genetics, McGill University, Montreal, Canada
4
Inozyme Pharma Inc., Boston, USA
5
Department of Pediatrics, McGill University, Montreal, Canada
advent of next-generation sequencing (NGS), and availability of disease gene panels, it is now feasible to identify causative mutations in an affordable manner, allowing early intervention with targeted treatment strategies, where possible. Interestingly, it was discovered that NMD (premature STOP codons) can be overcome by an unanticipated property of aminoglycoside (AG) antibiotics [5]. AGs bind to a region known as the decoding site on the small subunit of mammalian ribosomes, which monitors proper codon-anticodon interaction. The binding of AGs to the decoding site induces a conformational change that causes wobble in the strict pairing between transcript and cognate aminoacyl-tRNA. This allows the translational machinery to insert the intended amino acid, despite a one nucleotide mismatch, so that translation of the protein can be completed. For example, Brasell et al. sho
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