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The phenotypic spectrum of the m.3243A\u2009&gt;\u2009G mutation has since expanded to include a spectrum of neuromuscular and ocular manifestations, including reduced vision with retinal degeneration, the underlying mechanism of which remains unclear. We used dermal fibroblasts, from patients with retinal pathology secondary to the m.3243A\u2009&gt;\u2009G mutation to generate heteroplasmic induced pluripotent stem cell (hiPSC) clones. RPE cells differentiated from these hiPSCs contained morphologically abnormal mitochondria and melanosomes, and exhibited marked functional defects in phagocytosis of photoreceptor outer segments. These findings have striking similarities to the pathological abnormalities reported in RPE cells studied from post-mortem tissues of affected m.3243A\u2009&gt;\u2009G mutation carriers. Overall, our results indicate that RPE cells carrying the m.3243A\u2009&gt;\u2009G mutation have a reduced ability to perform the critical physiological function of phagocytosis. Aberrant melanosomal morphology may potentially have consequences on the ability of the cells to perform another important protective function, namely absorption of stray light. Our <jats:italic>in vitro<\/jats:italic> cell model could prove a powerful tool to further dissect the complex pathophysiological mechanisms that underlie the tissue specificity of the m.3243A\u2009&gt;\u2009G mutation, and importantly, allow the future testing of novel therapeutic agents.<\/jats:p>","DOI":"10.1038\/s41598-017-12396-2","type":"journal-article","created":{"date-parts":[[2017,9,20]],"date-time":"2017-09-20T09:41:06Z","timestamp":1505900466000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":27,"title":["Human iPSC disease modelling reveals functional and structural defects in retinal pigment epithelial cells harbouring the m.3243A\u2009&gt;\u2009G mitochondrial DNA mutation"],"prefix":"10.1038","volume":"7","author":[{"given":"Valeria","family":"Chichagova","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dean","family":"Hallam","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph","family":"Collin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adriana","family":"Buskin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriele","family":"Saretzki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lyle","family":"Armstrong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick","family":"Yu-Wai-Man","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Majlinda","family":"Lako","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David H.","family":"Steel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2017,9,26]]},"reference":[{"key":"12396_CR1","doi-asserted-by":"publisher","first-page":"753","DOI":"10.1002\/ana.24362","volume":"77","author":"GS Gorman","year":"2015","unstructured":"Gorman, G. 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Epidemiology of A3243G, the mutation for mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes: prevalence of the mutation in an adult population. Am. J. Hum. Genet. \n                           63, 447\u2013454, https:\/\/doi.org\/10.1086\/301959 (1998).","journal-title":"Am. J. Hum. Genet."},{"key":"12396_CR4","doi-asserted-by":"publisher","first-page":"7346","DOI":"10.1093\/nar\/gku390","volume":"42","author":"T Suzuki","year":"2014","unstructured":"Suzuki, T. A complete landscape of post-transcriptional modifications in mammalian mitochondrial tRNAs. Nucleic Acids Res \n                           42, 7346\u20137357, https:\/\/doi.org\/10.1093\/nar\/gku390 (2014).","journal-title":"Nucleic Acids Res"},{"key":"12396_CR5","doi-asserted-by":"publisher","first-page":"237","DOI":"10.4088\/PCC.v10n0309","volume":"10","author":"CG Bhuvaneswar","year":"2008","unstructured":"Bhuvaneswar, C. G., Goetz, J. L. & Stern, T. A. Multiple neurologic, psychiatric, and endocrine complaints in a young woman: a case discussion and review of the clinical features and management of mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke. Prim. Care. Companion. J. Clin. Psychiatry. \n                           10, 237\u2013244 (2008).","journal-title":"Prim. Care. Companion. J. Clin. Psychiatry."},{"key":"12396_CR6","doi-asserted-by":"publisher","first-page":"288","DOI":"10.1016\/j.ymgme.2016.06.003","volume":"118","author":"V Dvorakova","year":"2016","unstructured":"Dvorakova, V. et al. The phenotypic spectrum of fifty Czech m.3243A\u2009>\u2009G carriers. Mol. Genet. Metab. \n                           118, 288\u2013295, https:\/\/doi.org\/10.1016\/j.ymgme.2016.06.003 (2016).","journal-title":"Mol. Genet. Metab."},{"key":"12396_CR7","doi-asserted-by":"publisher","first-page":"121","DOI":"10.1136\/bjo.2008.154187","volume":"94","author":"MA Gronlund","year":"2010","unstructured":"Gronlund, M. A. et al. Ophthalmological findings in children and young adults with genetically verified mitochondrial disease. Br. J. Ophthalmol. \n                           94, 121\u2013127, https:\/\/doi.org\/10.1136\/bjo.2008.154187 (2010).","journal-title":"Br. J. Ophthalmol."},{"key":"12396_CR8","doi-asserted-by":"publisher","unstructured":"Zhu, C. C., Traboulsi, E. I. & Parikh, S. Ophthalmological findings in 74 patients with mitochondrial disease. Ophthalmic Genet., 1\u20133, doi:https:\/\/doi.org\/10.3109\/13816810.2015.1130153 (2016).","DOI":"10.3109\/13816810.2015.1130153"},{"key":"12396_CR9","doi-asserted-by":"publisher","first-page":"789","DOI":"10.1007\/s00401-016-1625-2","volume":"132","author":"P Yu-Wai-Man","year":"2016","unstructured":"Yu-Wai-Man, P. et al. A neurodegenerative perspective on mitochondrial optic neuropathies. 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