{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T10:51:42Z","timestamp":1785754302351,"version":"3.56.0"},"reference-count":11,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2020,11,7]],"date-time":"2020-11-07T00:00:00Z","timestamp":1604707200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2020,11,7]],"date-time":"2020-11-07T00:00:00Z","timestamp":1604707200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100009702","name":"Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100009702","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["BMC Neurol"],"published-print":{"date-parts":[[2020,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n<jats:sec>\n<jats:title>Background<\/jats:title>\n<jats:p>Mutations in <jats:italic>TGM6<\/jats:italic> gene, encoding for transglutaminase 6 (TG6), have been implicated in the pathogenesis of spinocerebellar ataxia type 35 (SCA35), a rare autosomal dominant disease marked by cerebellar degeneration and characterized by postural instability, incoordination of gait, features of cerebellar dysfunction and pyramidal signs.<\/jats:p>\n<\/jats:sec>\n<jats:sec>\n<jats:title>Case presentation<\/jats:title>\n<jats:p>Here we report the case of an Italian patient with late-onset, slowly progressive cerebellar features, including gait ataxia, scanning speech and ocular dysmetria and pyramidal tract signs. Whole exome sequencing revealed the rare heterozygous c.1024C\u2009&gt;\u2009T (p.R342W) variant of <jats:italic>TGM6<\/jats:italic>, located at a highly evolutionary conserved position and predicted as pathogenic by in silico tools. Expression of TG6-R342W mutant in HEK293T cells led to a significant reduction of transamidase activity compared to wild-type TG6.<\/jats:p>\n<\/jats:sec>\n<jats:sec>\n<jats:title>Conclusion<\/jats:title>\n<jats:p>This finding extends SCA35 genetic landscape, highlighting the importance of <jats:italic>TGM6<\/jats:italic> screening in undiagnosed late-onset and slowly progressive cerebellar ataxias.<\/jats:p>\n<\/jats:sec>","DOI":"10.1186\/s12883-020-01964-1","type":"journal-article","created":{"date-parts":[[2020,11,7]],"date-time":"2020-11-07T08:02:51Z","timestamp":1604736171000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["A case report of late-onset cerebellar ataxia associated with a rare p.R342W TGM6 (SCA35) mutation"],"prefix":"10.1186","volume":"20","author":[{"given":"Arianna","family":"Manini","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tommaso","family":"Bocci","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alice","family":"Migazzi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edoardo","family":"Monfrini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dario","family":"Ronchi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giulia","family":"Franco","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"De Rosa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ferdinando","family":"Sartucci","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alberto","family":"Priori","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefania","family":"Corti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giacomo Pietro","family":"Comi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nereo","family":"Bresolin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manuela","family":"Basso","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6478-026X","authenticated-orcid":false,"given":"Alessio","family":"Di Fonzo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,11,7]]},"reference":[{"issue":"9","key":"1964_CR1","doi-asserted-by":"publisher","first-page":"885","DOI":"10.1016\/S1474-4422(10)70183-6","volume":"9","author":"A Durr","year":"2010","unstructured":"Durr A. Autosomal dominant cerebellar ataxias: polyglutamine expansions and beyond. Lancet Neurol. 2010;9(9):885\u201394 Available from: \nhttps:\/\/linkinghub.elsevier.com\/retrieve\/pii\/S1474442210701836\n\n.","journal-title":"Lancet Neurol"},{"key":"1964_CR2","doi-asserted-by":"publisher","unstructured":"Wang JL, Yang X, Xia K, Hu ZM, Weng L, Jin X, et al. TGM6 identified as a novel causative gene of spinocerebellar ataxias using exome sequencing. Brain 2010;133(12):3510\u20133518. Available from: https:\/\/academic.oup.com\/brain\/article-lookup\/doi\/\nhttps:\/\/doi.org\/10.1093\/brain\/awq323\n\n.","DOI":"10.1093\/brain\/awq323"},{"key":"1964_CR3","doi-asserted-by":"publisher","unstructured":"Guo Y-C, Lin J-J, Liao Y-C, Tsai P-C, Lee Y-C, Soong B-W. Spinocerebellar ataxia 35: novel mutations in TGM6 with clinical and genetic characterization. Neurol Int 2014;83(17):1554\u20131561. Available from: http:\/\/www.neurology.org\/cgi\/doi\/\nhttps:\/\/doi.org\/10.1212\/WNL.0000000000000909\n\n.","DOI":"10.1212\/WNL.0000000000000909"},{"issue":"W1","key":"1964_CR4","doi-asserted-by":"publisher","first-page":"W597","DOI":"10.1093\/nar\/gkt376","volume":"41","author":"H McWilliam","year":"2013","unstructured":"McWilliam H, Li W, Uludag M, Squizzato S, Park YM, Buso N, et al. Analysis tool web services from the EMBL-EBI. Nucleic Acids Res. 2013;41(W1):W597\u2013600 Available from: \nhttp:\/\/academic.oup.com\/nar\/article\/41\/W1\/W597\/1095852\/Analysis-Tool-Web-Services-from-the-EMBLEBI\n\n.","journal-title":"Nucleic Acids Res"},{"issue":"19","key":"1964_CR5","doi-asserted-by":"publisher","first-page":"3749","DOI":"10.1093\/hmg\/ddx259","volume":"26","author":"D Tripathy","year":"2017","unstructured":"Tripathy D, Vignoli B, Ramesh N, Polanco MJ, Coutelier M, Stephen CD, et al. Mutations in TGM6 induce the unfolded protein response in SCA35. Hum Mol Genet. 2017;26(19):3749\u201362 Available from: \nhttp:\/\/academic.oup.com\/hmg\/article\/26\/19\/3749\/3930118\/Mutations-in-TGM6-induce-the-unfolded-protein\n\n.","journal-title":"Hum Mol Genet"},{"key":"1964_CR6","doi-asserted-by":"publisher","first-page":"84","DOI":"10.1016\/j.parkreldis.2017.07.001","volume":"46","author":"Z Yang","year":"2018","unstructured":"Yang Z, Shi M, Liu Y, Wang Y, Luo H, Wang Z, et al. TGM6 gene mutations in undiagnosed cerebellar ataxia patients. Parkinsonism Relat Disord. 2018;46:84\u20136 Available from: \nhttps:\/\/linkinghub.elsevier.com\/retrieve\/pii\/S1353802017302341\n\n.","journal-title":"Parkinsonism Relat Disord"},{"key":"1964_CR7","doi-asserted-by":"publisher","first-page":"42","DOI":"10.1016\/j.parkreldis.2019.01.013","volume":"63","author":"JLF Fung","year":"2019","unstructured":"Fung JLF, Tsang MHY, Leung GKC, Yeung KS, Mak CCY, Fung CW, et al. A significant inflation in TGM6 genetic risk casts doubt in its causation in spinocerebellar ataxia type 35. Parkinsonism Relat Disord. 2019;63:42\u20135 Available from: \nhttps:\/\/linkinghub.elsevier.com\/retrieve\/pii\/S1353802019300136\n\n.","journal-title":"Parkinsonism Relat Disord"},{"key":"1964_CR8","doi-asserted-by":"publisher","unstructured":"Li M, Pang S, Song Y, Kung M, Ho S-L, Sham P-C. Whole exome sequencing identifies a novel mutation in the transglutaminase 6 gene for spinocerebellar ataxia in a Chinese family. Clin Genet 2013;83(3):269\u2013273. Available from: http:\/\/doi.wiley.com\/\nhttps:\/\/doi.org\/10.1111\/j.1399-0004.2012.01895.x\n\n.","DOI":"10.1111\/j.1399-0004.2012.01895.x"},{"key":"1964_CR9","doi-asserted-by":"publisher","unstructured":"Lin C-C, Gan S-R, Gupta D, Alaedini A, Green PH, Kuo S-H. Hispanic Spinocerebellar Ataxia type 35 (SCA35) with a novel Frameshift mutation. Cerebellum 2019;18(2):291\u2013294. Available from: http:\/\/link.springer.com\/\nhttps:\/\/doi.org\/10.1007\/s12311-018-0978-6\n\n.","DOI":"10.1007\/s12311-018-0978-6"},{"key":"1964_CR10","doi-asserted-by":"publisher","first-page":"118","DOI":"10.1016\/j.parkreldis.2017.01.014","volume":"37","author":"A Fasano","year":"2017","unstructured":"Fasano A, Hodaie M, Munhoz RP, Rohani M. SCA 35 presenting as isolated treatment-resistant dystonic hand tremor. Parkinsonism Relat Disord. 2017;37:118\u20139 Available from: \nhttps:\/\/linkinghub.elsevier.com\/retrieve\/pii\/S1353802017300330\n\n.","journal-title":"Parkinsonism Relat Disord"},{"key":"1964_CR11","doi-asserted-by":"publisher","unstructured":"De Marinis M, Stocchi F, Gregori B, Accornero N. Sympathetic skin response and cardiovascular autonomic function tests in Parkinson\u2019s disease and multiple system atrophy with autonomic failure. Mov Disord 2000 Nov;15(6):1215\u20131220. Available from: http:\/\/doi.wiley.com\/\nhttps:\/\/doi.org\/10.1002\/1531-8257%28200011%2915%3A6%3C1215%3A%3AAID-MDS1023%3E3.0.CO%3B2-J\n\n.","DOI":"10.1002\/1531-8257%28200011%2915%3A6%3C1215%3A%3AAID-MDS1023%3E3.0.CO%3B2-J"}],"container-title":["BMC Neurology"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1186\/s12883-020-01964-1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/article\/10.1186\/s12883-020-01964-1\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1186\/s12883-020-01964-1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2020,11,7]],"date-time":"2020-11-07T08:03:17Z","timestamp":1604736197000},"score":1,"resource":{"primary":{"URL":"https:\/\/bmcneurol.biomedcentral.com\/articles\/10.1186\/s12883-020-01964-1"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,11,7]]},"references-count":11,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2020,12]]}},"alternative-id":["1964"],"URL":"https:\/\/doi.org\/10.1186\/s12883-020-01964-1","relation":{},"ISSN":["1471-2377"],"issn-type":[{"value":"1471-2377","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,11,7]]},"assertion":[{"value":"28 May 2020","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"16 October 2020","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"7 November 2020","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The \u201cComitato Etico Milano Area 2 Fondazione IRCCS Ca\u2019 Granda Ospedale Maggiore Policlinico\u201d (Milan, Italy) approved the study. The patient and his cousins provided written informed consent to participate to the study.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Written informed consent was obtained from the patient and his cousins included in the study.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"A.D.F. declares to be a member of the editorial board (Associate Editor) of <i>BMC Neurology<\/i>. The other authors declare that they have no conflict of interest.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"408"}}