Generation of an induced pluripotent stem cell line from a 39-year-old female patient with severe-to-profound non-syndromic sensorineural hearing loss and a A1555G mutation in the mitochondrial MTRNR1 gene

Abstract

Sensorineural hearing loss (SNHL) is a prevalent form of deafness commonly arising from damage to the cochlear sensory hair cells and degeneration of the spiral ganglion neurons. In this study, Sendai virus was used to generate an induced pluripotent stem cell (iPSC) line from a 39-year-old female patient diagnosed with severe-to-profound, non-syndromic SNHL. The patient also carries a A1555G mutation in the mitochondrial 12S ribosome RNA gene (MTRNR1). This iPSC line was verified to express pluripotent markers, possess normal karyotype, harbor the specific mutation and demonstrated the capacity to differentiate into three germ layers.

Induced Pluripotent Stem Cells, a Stepping Stone to In Vitro Human Models of Hearing Loss

“…The common marmoset, also amenable to genetic modification, has thus been proposed as a more predictive model of human cochlear development and pathology [ 21 , 22 ]. In addition, hiPSC lines are being generated from somatic cells obtained from patients with HL [ 89 , 90 , 91 , 92 , 93 ] and subsequently differentiated towards a range of different otic cell types [ 37 , 59 ], thus providing human cell-based models that overcome the limitations imposed by the complex anatomy of the inner ear and the lack of human tissue; very importantly, these cultures retain the genetic backgrounds and the mutations present in patients with hearing deficits, constituting an ideal substrate for studies on the molecular mechanisms that lead to syndromic or non-syndromic HL and the validation of therapeutic targets through the creation of isogenic control cell lines [ 59 , 88 , 94 ]. Additionally, they provide the means to model mutations within large non-coding chromosomic regions that would otherwise be very difficult to replicate.…”

“…Other mutations have been described in mitochondrial genes that have been associated with an increased susceptibility to presbycusis progression, noise- and ototoxin-induced SNHL [ 116 , 117 , 118 ]; most frequently, the development of symptoms depends on the convergence of these mutations with other factors such as exposure to ototoxins and/or high levels of noise, or the presence of other modifier genes [ 119 , 120 ]. Hsu and co-workers have established an hiPSC line that carries an A1555A > G mutation in the Mitochondrial 12S Ribosome RNA (MT-RNR 1) gene [ 93 ]. This is the most prevalent mutation in MT-RNR 1, and it results in increased binding of aminoglycoside antibiotics (AGs) to the mitochondrial ribosome and AG-induced HL; it is therefore important to identify MT-RNR1 variants that may render individuals more likely to develop AG-induced HL prior to the administration of this type of anti-infective [ 121 ].…”

“…This is the most prevalent mutation in MT-RNR 1, and it results in increased binding of aminoglycoside antibiotics (AGs) to the mitochondrial ribosome and AG-induced HL; it is therefore important to identify MT-RNR1 variants that may render individuals more likely to develop AG-induced HL prior to the administration of this type of anti-infective [ 121 ]. In turn, hiPSC lines such as the one developed by Hsu and co-workers (2017) could become very useful tools in screening programs to evaluate the ototoxic potential of newly developed AGs [ 93 ]. Highly illustrative of the complexity of the interactions leading to hearing impairment is the work conducted by Chen and Guan (2022); these authors generated hiPSCs from individuals who either carried an A1555A > G mutation or that same mutation coupled to a mutation (c.28G > T) in the TRNA5-Methyaminomethyl-2-Thiouridylate methyltransferase (TRMU) gene [ 119 ].…”

Mitochondrial Dysfunction and Therapeutic Targets in Auditory Neuropathy

“…Others such as gene therapy [107] and stem cell therapy [108] still have been studied. But auditory neuropathy treatment is still limited, requiring more exploration.…”

Cell models and drug discovery for mitochondrial diseases

“…Several other patientspecific iPSCs carrying mtDNA mutations and iPSCderived cell models have also been generated. These include a 2.5-kb deletion of mtDNA associated with Pearson bone marrow pancreatic syndrome (PS) (Cherry et al, 2013), the m.3243A>G variant in mitochondrial causing MELAS (Ma et al, 2015) or diabetes (Fujikura et al, 2012;Matsubara et al, 2018), the m.8344A>G variant correlated with myoclonic epilepsy with ragged red fibers (MERRF) syndrome (Chou et al, 2016(Chou et al, , 2018, the m.11778G>A variant implicated in LHON (Lu et al, 2018;Wu et al, 2018), and the m.1555A>G variant related to sensorineural hearing loss (SNHL) (Hsu et al, 2017).…”