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It is a unique example of an immune deficiency that is linked to dysfunctional mitochondrial energy metabolism and caused by adenylate kinase 2 <jats:bold>(<\/jats:bold>AK2) deficiency. It is characterized by an early differentiation arrest in the myeloid lineage, impaired lymphoid maturation, and sensorineural hearing loss. In this study, a novel <jats:italic>AK2<\/jats:italic> homozygous mutation, c.622\u2009T\u2009&gt;\u2009C [p.Ser208Pro], was identified in an Old Order Amish patient through whole exome sequencing. Functional studies showed that the patient\u2019s cells have no detectable AK2 protein, as well as low oxygen consumption rate (OCR), extracellular acidification rate (ECAR) and proton production rate (PPR). An increased production of reactive oxygen species, mitochondrial membrane permeability, and mitochondrial mass, and decreased ATP production, were also observed. The results confirm the pathogenicity of the <jats:italic>AK2<\/jats:italic> mutation and demonstrate that reticular dysgenesis should be considered in Amish individuals presenting with immune deficiency. We also describe other pathophysiological aspects of AK2 deficiency not previously reported.<\/jats:p>","DOI":"10.1038\/s41598-019-51922-2","type":"journal-article","created":{"date-parts":[[2019,10,31]],"date-time":"2019-10-31T11:08:43Z","timestamp":1572520123000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Reticular Dysgenesis and Mitochondriopathy Induced by Adenylate Kinase 2 Deficiency with Atypical Presentation"],"prefix":"10.1038","volume":"9","author":[{"given":"Lina","family":"Ghaloul-Gonzalez","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0096-5959","authenticated-orcid":false,"given":"Al-Walid","family":"Mohsen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anuradha","family":"Karunanidhi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bianca","family":"Seminotti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hey","family":"Chong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suneeta","family":"Madan-Khetarpal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica","family":"Sebastian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catherine Walsh","family":"Vockley","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5698-3702","authenticated-orcid":false,"given":"Miguel","family":"Reyes-M\u00fagica","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9714-4454","authenticated-orcid":false,"given":"Mark T.","family":"Vander Lugt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jerry","family":"Vockley","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2019,10,31]]},"reference":[{"key":"51922_CR1","doi-asserted-by":"publisher","first-page":"101","DOI":"10.1038\/ng.265","volume":"41","author":"U Pannicke","year":"2009","unstructured":"Pannicke, U. et al. Reticular dysgenesis (aleukocytosis) is caused by mutations in the gene encoding mitochondrial adenylate kinase 2. Nat. Genet. 41, 101\u2013105 (2009).","journal-title":"Nat. Genet."},{"key":"51922_CR2","doi-asserted-by":"publisher","first-page":"4081","DOI":"10.1074\/jbc.M110.134106","volume":"286","author":"A Burkart","year":"2011","unstructured":"Burkart, A., Shi, X., Chouinard, M. & Corvera, S. Adenylate kinase 2 links mitochondrial energy metabolism to the induction of the unfolded protein response. J. Biol. Chem. 286, 4081\u20134089 (2011).","journal-title":"J. Biol. Chem."},{"key":"51922_CR3","doi-asserted-by":"publisher","DOI":"10.1038\/cddis.2015.211","volume":"6","author":"E Six","year":"2015","unstructured":"Six, E. et al. AK2 deficiency compromises the mitochondrial energy metabolism required for differentiation of human neutrophil and lymphoid lineages. 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