{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,8,31]],"date-time":"2025-08-31T23:26:43Z","timestamp":1756682803214,"version":"3.40.5"},"reference-count":56,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2022,9,13]],"date-time":"2022-09-13T00:00:00Z","timestamp":1663027200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100003968","name":"Iran National Science Foundation","doi-asserted-by":"publisher","award":["4005531"],"award-info":[{"award-number":["4005531"]}],"id":[{"id":"10.13039\/501100003968","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Euro J of Neurology"],"published-print":{"date-parts":[[2022,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background and purpose<\/jats:title><jats:p>Spinal\u2013bulbar muscular atrophy (SBMA) (Kennedy's disease) is a motor neuron disease. Kennedy's disease is nearly exclusively caused by mutations in the androgen receptor encoding gene (<jats:italic>AR<\/jats:italic>). The results of studies aimed at identification of the genetic cause of a disease that best approximates SBMA in a pedigree (four patients) without mutations in <jats:italic>AR<\/jats:italic> are reported.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Clinical investigations included thorough neurological and non\u2010neurological examinations and testing. Genetic analysis was performed by exome sequencing using standard protocols. <jats:italic>UBA1<\/jats:italic> mutations were modeled on the crystal structure of UBA1.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The clinical features of the patients are described in detail. A missense mutation in <jats:italic>UBA1<\/jats:italic> (c.T1499C; p.Ile500Thr) was identified as the probable cause of the non\u2010Kennedy SBMA in the pedigree. Like <jats:italic>AR<\/jats:italic>, <jats:italic>UBA1<\/jats:italic> is positioned on chromosome X. <jats:italic>UBA1<\/jats:italic> is a highly conserved gene. It encodes ubiquitin\u2010like modifier activating enzyme 1 (UBA1) which is the major E1 enzyme of the ubiquitin\u2013proteasome system. Interestingly, <jats:italic>UBA1<\/jats:italic> mutations can also cause infantile\u2010onset X\u2010linked spinal muscular atrophy (XL\u2010SMA). The mutation identified here and the XL\u2010SMA causative mutations were shown to affect amino acids positioned in the vicinity of UBA1's ATP binding site and to cause structural changes.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p><jats:italic>UBA1<\/jats:italic> was identified as a novel SBMA causative gene. The gene affects protein homeostasis which is one of most important components of the pathology of neurodegeneration. The contribution of this same gene to the etiology of XL\u2010SMA is discussed.<\/jats:p><\/jats:sec>","DOI":"10.1111\/ene.15528","type":"journal-article","created":{"date-parts":[[2022,8,23]],"date-time":"2022-08-23T08:42:16Z","timestamp":1661244136000},"page":"3556-3563","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Identification of <scp><i>UBA1<\/i><\/scp> as the causative gene of an X\u2010linked <scp>non\u2010Kennedy<\/scp> spinal\u2013bulbar muscular atrophy"],"prefix":"10.1111","volume":"29","author":[{"given":"Marzieh","family":"Khani","sequence":"first","affiliation":[{"name":"School of Biology, College of Science University of Tehran  Tehran Iran"},{"name":"Iranian Neuromusclar Research Center Tehran University of Medical Sciences  Tehran 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