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Recent research revealed an overload of missense variants in the <jats:italic>ANK2<\/jats:italic> gene in individuals with severe tinnitus. <jats:italic>ANK2<\/jats:italic>, encoding ankyrin-B, regulates axon branching and inhibits microtubule invasion. Missense mutations in ANK2 may promote excessive axonal branching and the formation of excitatory synapses. This study aims to generate a patient-derived iPSC model from an individual with severe tinnitus and to differentiate these cells into otic-neural progenitors and inner ear neurons. We successfully generated a severe tinnitus cellular model through cell reprogramming. Using a two-stage neural differentiation protocol, we differentiated these cells into otic-neural progenitors and neuron-like cells. We confirmed the expression of genes, proteins, and cellular markers, including <jats:italic>ANK2<\/jats:italic>, otic-neural progenitors, and neuron-like cells through qPCR and immunostaining. Our analysis revealed higher <jats:italic>ANK2<\/jats:italic> expression in the control cell line compared to the patient cell line. Although both lines formed multipolar neurons, the patient cell line displayed a unique pattern of closely grouped neurons with increased neuronal projections and dendrites compared to the control. This cellular model provides a valuable tool for studying the cellular and molecular changes associated with the <jats:italic>ANK2<\/jats:italic> gene. It holds great promise for the development of novel drug and gene-based therapies for severe tinnitus.<\/jats:p>","DOI":"10.1007\/s12035-024-04674-8","type":"journal-article","created":{"date-parts":[[2025,1,15]],"date-time":"2025-01-15T22:07:50Z","timestamp":1736978870000},"page":"6467-6477","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A Neuron-Like Cellular Model for Severe Tinnitus Associated with Rare Variations in the ANK2 Gene"],"prefix":"10.1007","volume":"62","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2506-1120","authenticated-orcid":false,"given":"Mar","family":"Lamolda","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6104-0941","authenticated-orcid":false,"given":"Lidia","family":"Frejo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5505-8734","authenticated-orcid":false,"given":"Juan","family":"Martin-Lagos","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-7541-6889","authenticated-orcid":false,"given":"Francisca E.","family":"Cara","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6068-8965","authenticated-orcid":false,"given":"Alvaro","family":"Gallego-Martinez","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8583-1430","authenticated-orcid":false,"given":"Jose A.","family":"Lopez-Escamez","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2025,1,15]]},"reference":[{"key":"4674_CR1","doi-asserted-by":"publisher","first-page":"711","DOI":"10.1016\/j.amjmed.2010.02.015","volume":"123","author":"J Shargorodsky","year":"2010","unstructured":"Shargorodsky J, Curhan GC, Farwell WR (2010) Prevalence and characteristics of tinnitus among US adults. 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