{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,8]],"date-time":"2025-10-08T22:26:26Z","timestamp":1759962386343,"version":"3.41.2"},"reference-count":21,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2019,5,20]],"date-time":"2019-05-20T00:00:00Z","timestamp":1558310400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["KAKENHI\/16K10202"],"award-info":[{"award-number":["KAKENHI\/16K10202"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Molec Gen &amp; Gen Med"],"published-print":{"date-parts":[[2019,7]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>The tricarboxylic acid (TCA) cycle is a sequence of catabolic reactions within the mitochondrial matrix, and is a central pathway for cellular energy metabolism. Genetic defects affecting the TCA cycle are known to cause severe multisystem disorders.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We performed whole exome sequencing of genomic DNA of a patient with progressive cerebellar and cerebral atrophy, hypotonia, ataxia, seizure disorder, developmental delay, ophthalmological abnormalities and hearing loss. We also performed biochemical studies using patient fibroblasts.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We identified new compound heterozygous mutations (c.1534G\u00a0&gt;\u00a0A, p.Asp512Asn and c.1997G\u00a0&gt;\u00a0C, p.Gly666Ala) in <jats:italic>ACO2,<\/jats:italic> which encodes aconitase 2, a component of the TCA cycle. In patient fibroblasts, the aconitase activity was reduced to 15% of that of the control, and the aconitase 2 level decreased to 36% of that of the control. As such a decrease in aconitase 2 in patient fibroblasts was partially restored by proteasome inhibition, mutant aconitase 2 was suggested to be relatively unstable and rapidly degraded after being synthesized. In addition, the activity of the father\u2010derived variant of aconitase 2 (p.Gly666Ala), which had a mutation near the active center, was 55% of that of wild\u2010type.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>The marked reduction of aconitase activity in patient fibroblasts was due to the combination of decreased aconitase 2 amount and activity due to mutations. Reduced aconitase activity directly suppresses the TCA cycle, resulting in mitochondrial dysfunction, which may lead to symptoms similar to those observed in mitochondrial diseases.<\/jats:p><\/jats:sec>","DOI":"10.1002\/mgg3.698","type":"journal-article","created":{"date-parts":[[2019,5,20]],"date-time":"2019-05-20T10:28:54Z","timestamp":1558348134000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Identification of novel compound heterozygous mutations in <i>ACO2<\/i> in a patient with progressive cerebral and cerebellar atrophy"],"prefix":"10.1002","volume":"7","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6768-2921","authenticated-orcid":false,"given":"Masahide","family":"Fukada","sequence":"first","affiliation":[{"name":"Department of Embryology Institute for Developmental Research, Aichi Human Service Center Kasugai Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Keitaro","family":"Yamada","sequence":"additional","affiliation":[{"name":"Department of Pediatric Neurology Aichi Prefectural Colony Central Hospital, Aichi Human Service Center Kasugai Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shima","family":"Eda","sequence":"additional","affiliation":[{"name":"Department of Embryology Institute for Developmental Research, Aichi Human Service Center Kasugai Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ken","family":"Inoue","sequence":"additional","affiliation":[{"name":"Department of Mental Retardation and Birth Defect Research National Center of Neurology and Psychiatry Kodaira, Tokyo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chihiro","family":"Ohba","sequence":"additional","affiliation":[{"name":"Department of Human Genetics Yokohama City University Graduate School of Medicine Yokohama Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Naomichi","family":"Matsumoto","sequence":"additional","affiliation":[{"name":"Department of Human Genetics Yokohama City University Graduate School of Medicine Yokohama Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0723-0960","authenticated-orcid":false,"given":"Hirotomo","family":"Saitsu","sequence":"additional","affiliation":[{"name":"Department of Biochemistry Hamamatsu University School of Medicine Hamamatsu Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Atsuo","family":"Nakayama","sequence":"additional","affiliation":[{"name":"Department of Embryology Institute for Developmental Research, Aichi Human Service Center Kasugai Japan"},{"name":"Department of Neurochemistry Nagoya University Graduate School of Medicine Nagoya Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2019,5,20]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0176363"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth0410-248"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI117261"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng1095-144"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1086\/430843"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuropharm.2016.08.018"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/jhg.2016.1"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2009.86"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1021\/bi00125a014"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1212\/NXG.0000000000000225"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1136\/jmedgenet-2014-102532"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.9319"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1086\/519222"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molmed.2011.06.001"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.1002\/prot.340050406"},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymgme.2016.03.004"},{"key":"e_1_2_7_18_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1469-1809.1975.tb00122.x"},{"key":"e_1_2_7_19_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1469-1809.1977.tb01857.x"},{"key":"e_1_2_7_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2012.01.009"},{"key":"e_1_2_7_21_1","doi-asserted-by":"publisher","DOI":"10.1177\/0883073817711527"},{"key":"e_1_2_7_22_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.pathol.4.110807.092314"}],"container-title":["Molecular Genetics &amp; 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