{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T21:57:55Z","timestamp":1791496675965,"version":"4.3.4"},"reference-count":39,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2017,12,2]],"date-time":"2017-12-02T00:00:00Z","timestamp":1512172800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100000272","name":"National Institute for Health Research","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000272","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000272","name":"National Institute for Health Research","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000272","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000765","name":"University College London","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000765","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":[[2018,1]]},"abstract":"Background and purpose<\/jats:title>Mutations in the small heat\u2010shock protein 22 gene (HSPB<\/jats:styled-content>8<\/jats:italic>) have been associated with Charcot\u2010Marie\u2010Tooth disease type 2L, distal hereditary motor neuropathy (dHMN) type II<\/jats:styled-content>a and, more recently, distal myopathy\/myofibrillar myopathy (MFM<\/jats:styled-content>) with protein aggregates and TDP<\/jats:styled-content>\u201043 inclusions. The aim was to report a novel family with HSPB<\/jats:styled-content>8<\/jats:italic>K141E<\/jats:sup>\u2010related dHMN\/MFM<\/jats:styled-content> and to investigate, in a patient muscle biopsy, whether the presence of protein aggregates was paralleled by altered TDP<\/jats:styled-content>\u201043 function.<\/jats:p><\/jats:sec>Methods<\/jats:title>We reviewed clinical and genetic data. We assessed TDP<\/jats:styled-content>\u201043 expression by qPCR<\/jats:styled-content> and alternative splicing of four previously validated direct TDP<\/jats:styled-content>\u201043 target exons in four genes by reverse transcriptase\u2013polymerase chain reaction.<\/jats:p><\/jats:sec>Results<\/jats:title>The triplets and their mother presented in the second to third decade of life with progressive weakness affecting distal and proximal lower limb and truncal muscles. Nerve conduction study showed a motor axonal neuropathy. The clinical features, moderately raised creatin kinase levels, selective pattern of muscle involvement on magnetic resonance imaging and pathological changes on muscle biopsy, including the presence of protein aggregates, supported the diagnosis of a contemporary primary muscle involvement. In affected muscle tissue we observed a consistent alteration of TDP<\/jats:styled-content>\u201043\u2010dependent splicing in three out of four TDP<\/jats:styled-content>\u201043\u2010target transcripts (POLDIP<\/jats:styled-content>3<\/jats:italic>, FNIP<\/jats:styled-content>1<\/jats:italic> and BRD<\/jats:styled-content>8<\/jats:italic>), as well as a significant decrease of TDP<\/jats:styled-content>\u201043 mRNA<\/jats:styled-content> levels.<\/jats:p><\/jats:sec>Conclusions<\/jats:title>Our study confirmed the role of mutated HSPB<\/jats:styled-content>8 as a cause of a combined neuromuscular disorder encompassing dHMN and MFM<\/jats:styled-content> with protein aggregates. We identified impaired RNA<\/jats:styled-content> metabolism, secondary to TDP<\/jats:styled-content>\u201043 loss of function, as a possible pathological mechanism of HSPB<\/jats:styled-content>8<\/jats:italic>K141E<\/jats:sup> toxicity, leading to muscle and nerve degeneration.<\/jats:p><\/jats:sec>","DOI":"10.1111\/ene.13478","type":"journal-article","created":{"date-parts":[[2017,10,13]],"date-time":"2017-10-13T17:06:40Z","timestamp":1507914400000},"page":"154-163","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":36,"title":["Altered TDP<\/scp>\u201043\u2010dependent splicing in HSPB<\/scp>8<\/i>\u2010related distal hereditary motor neuropathy and myofibrillar myopathy"],"prefix":"10.1111","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2208-5311","authenticated-orcid":false,"given":"A.","family":"Cortese","sequence":"first","affiliation":[{"name":"C. Mondino National Neurological Institute Foundation IRCCS Pavia Italy"},{"name":"MRC Centre for Neuromuscular Diseases UCL Institute of Neurology London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M.","family":"Laur\u00e0","sequence":"additional","affiliation":[{"name":"MRC Centre for Neuromuscular Diseases UCL Institute of Neurology London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C.","family":"Casali","sequence":"additional","affiliation":[{"name":"Department of Medical and Surgical Sciences and Biotechnologies Sapienza University of Rome Latina Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"I.","family":"Nishino","sequence":"additional","affiliation":[{"name":"Department of Neuromuscular Research National Center of Neurology and Psychiatry National Institute of Neuroscience Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Y. K.","family":"Hayashi","sequence":"additional","affiliation":[{"name":"Department of Pathophysiology Tokyo Medical University Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S.","family":"Magri","sequence":"additional","affiliation":[{"name":"Unit of Rare Neurodegenerative and Neurometabolic Diseases IRCCS Foundation C. Besta Neurological Institute Milan Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"F.","family":"Taroni","sequence":"additional","affiliation":[{"name":"Unit of Rare Neurodegenerative and Neurometabolic Diseases IRCCS Foundation C. Besta Neurological Institute Milan Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C.","family":"Stuani","sequence":"additional","affiliation":[{"name":"International Centre for Genetic Engineering and Biotechnology (ICGEB) Trieste Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"P.","family":"Saveri","sequence":"additional","affiliation":[{"name":"Unit of Rare Neurodegenerative and Neurometabolic Diseases IRCCS Foundation C. Besta Neurological Institute Milan Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M.","family":"Moggio","sequence":"additional","affiliation":[{"name":"Neuromuscular and Rare Diseases Unit Department of Neuroscience Fondazione IRCCS Ca\u2019 Granda, Ospedale Maggiore Policlinico Milan Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M.","family":"Ripolone","sequence":"additional","affiliation":[{"name":"Neuromuscular and Rare Diseases Unit Department of Neuroscience Fondazione IRCCS Ca\u2019 Granda, Ospedale Maggiore Policlinico Milan Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A.","family":"Prelle","sequence":"additional","affiliation":[{"name":"Department of Neurology Ospedale Maggiore Crema Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C.","family":"Pisciotta","sequence":"additional","affiliation":[{"name":"Unit of Rare Neurodegenerative and Neurometabolic Diseases IRCCS Foundation C. Besta Neurological Institute Milan Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A.","family":"Sagnelli","sequence":"additional","affiliation":[{"name":"Unit of Rare Neurodegenerative and Neurometabolic Diseases IRCCS Foundation C. Besta Neurological Institute Milan Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A.","family":"Pichiecchio","sequence":"additional","affiliation":[{"name":"C. Mondino National Neurological Institute Foundation IRCCS Pavia Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. M.","family":"Reilly","sequence":"additional","affiliation":[{"name":"MRC Centre for Neuromuscular Diseases UCL Institute of Neurology London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"E.","family":"Buratti","sequence":"additional","affiliation":[{"name":"International Centre for Genetic Engineering and Biotechnology (ICGEB) Trieste Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"D.","family":"Pareyson","sequence":"additional","affiliation":[{"name":"Unit of Rare Neurodegenerative and Neurometabolic Diseases IRCCS Foundation C. Besta Neurological Institute Milan Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2017,12,2]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng1328"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00439-004-1218-3"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000002324"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-017-1724-8"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamaneurol.2015.0178"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.2089"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkv814"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng1354"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neurobiolaging.2013.12.029"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1097\/NEN.0b013e3181996d8f"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/nn.2778"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/nn.2779"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkx477"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mrrev.2014.02.004"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1529-8027.2012.00409.x"},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2009.03.006"},{"key":"e_1_2_7_18_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng1332"},{"key":"e_1_2_7_19_1","doi-asserted-by":"crossref","first-page":"857","DOI":"10.1016\/j.neuron.2010.11.036","article-title":"Exome sequencing reveals VCP mutations as a cause of familial ALS","volume":"9","author":"Johnson JO","year":"2010","journal-title":"Neuron"},{"key":"e_1_2_7_20_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awu224"},{"key":"e_1_2_7_21_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1134108"},{"key":"e_1_2_7_22_1","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.3004052"},{"key":"e_1_2_7_23_1","first-page":"96","article-title":"Progress and problems in muscle glycogenoses","volume":"30","author":"DiMauro S","year":"2011","journal-title":"Acta Myol"},{"key":"e_1_2_7_24_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awu279"},{"key":"e_1_2_7_25_1","unstructured":"FrasquetM MuelasN SiveraR et al.Description of a cluster of patients with the HSPB1 p.R140G mutation. 6th CMTR Meeting Venice Sept. 2016."},{"key":"e_1_2_7_26_1","doi-asserted-by":"publisher","DOI":"10.1111\/jns.12139"},{"key":"e_1_2_7_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nmd.2011.05.002"},{"key":"e_1_2_7_28_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.20376"},{"key":"e_1_2_7_29_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.10767"},{"key":"e_1_2_7_30_1","doi-asserted-by":"publisher","DOI":"10.1002\/mus.21842"},{"key":"e_1_2_7_31_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nmd.2013.02.010"},{"key":"e_1_2_7_32_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.24255"},{"key":"e_1_2_7_33_1","doi-asserted-by":"crossref","first-page":"598","DOI":"10.2174\/1566524014666140603100131","article-title":"Myopathic involvement and mitochondrial pathology in Kennedy disease and in other motor neuron diseases","volume":"14","author":"Orsucci D","year":"2014","journal-title":"Curr Mol Med"},{"key":"e_1_2_7_34_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1423-0410.1981.tb00728.x"},{"key":"e_1_2_7_35_1","doi-asserted-by":"publisher","DOI":"10.1038\/6799"},{"key":"e_1_2_7_36_1","doi-asserted-by":"publisher","DOI":"10.1002\/1531-8249(20010201)49:2<245::AID-ANA45>3.0.CO;2-A"},{"key":"e_1_2_7_37_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/9.9.1453"},{"key":"e_1_2_7_38_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng1514"},{"key":"e_1_2_7_39_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng1657"},{"key":"e_1_2_7_40_1","unstructured":"MademanI DeconinckT GeuensT et al.HNRNPA1 mutations expand the spectrum of motor neuron diseases. 6th CMTR Meeting Venice Sept. 2016."}],"container-title":["European Journal of Neurology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1111%2Fene.13478","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/ene.13478","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,24]],"date-time":"2023-09-24T15:28:41Z","timestamp":1695569321000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/ene.13478"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,12,2]]},"references-count":39,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2018,1]]}},"alternative-id":["10.1111\/ene.13478"],"URL":"https:\/\/doi.org\/10.1111\/ene.13478","archive":["Portico"],"relation":{},"ISSN":["1351-5101","1468-1331"],"issn-type":[{"value":"1351-5101","type":"print"},{"value":"1468-1331","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,12,2]]},"assertion":[{"value":"2017-06-08","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2017-09-07","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2017-12-02","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}