{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T02:19:04Z","timestamp":1790475544713,"version":"4.1.0"},"reference-count":42,"publisher":"Oxford University Press (OUP)","issue":"24","license":[{"start":{"date-parts":[[2021,7,23]],"date-time":"2021-07-23T00:00:00Z","timestamp":1626998400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/100004807","name":"DFG","doi-asserted-by":"publisher","award":["Fi572\/8-2"],"award-info":[{"award-number":["Fi572\/8-2"]}],"id":[{"id":"10.13039\/100004807","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001381","name":"Singapore National Research Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001381","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001349","name":"National Medical Research Council","doi-asserted-by":"publisher","award":["MOE2016-T3-1-005"],"award-info":[{"award-number":["MOE2016-T3-1-005"]}],"id":[{"id":"10.13039\/501100001349","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001349","name":"National Medical Research Council","doi-asserted-by":"publisher","award":["R-154-000-B48-114"],"award-info":[{"award-number":["R-154-000-B48-114"]}],"id":[{"id":"10.13039\/501100001349","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,11,30]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>A deficiency in Survival Motor Neuron (SMN) protein results in motor neuron loss in spinal muscular atrophy (SMA) patients. Human SMN is encoded by SMN1 and SMN2 that differ by a single C6T transition in a splice regulatory region of exon 7. In SMN2, exon 7 is skipped leading to an unstable protein, which cannot compensate for SMN1 loss in SMA patients. The disease severity of human SMA (Types 1\u20134) depends on the levels of SMN protein, with intermediate levels leading to delayed disease onset and extended life expectancy in Type 2 patients. We used homology directed repair (HDR) to generate a zebrafish mutant with intermediate Smn levels, to mimic intermediate, hSMN2 dependent forms of SMA. In the obtained smnA6Tind27 mutant zebrafish, Smn protein formed oligomers but protein levels dropped significantly at juvenile stages. Motor neurons and neuromuscular junctions (NMJ) also formed normally initially but motor neuron loss and locomotor deficiencies became evident at 21\u00a0days. Subsequent muscle wasting and early adult lethality also phenocopied intermediate forms of human SMA. Together, our findings are consistent with the interpretation that Smn is required for neuromuscular maintenance, and establish the smnA6Tind27 zebrafish mutant as a novel model for intermediate types of SMA. As this mutant allows studying the effect of late Smn loss on motor neurons, neuromuscular junctions, and muscle at advanced stages of the disease, it will be a valuable resource for testing new drugs targeted towards treating intermediate forms of SMA.<\/jats:p>","DOI":"10.1093\/hmg\/ddab212","type":"journal-article","created":{"date-parts":[[2021,7,20]],"date-time":"2021-07-20T19:32:58Z","timestamp":1626809578000},"page":"2488-2502","source":"Crossref","is-referenced-by-count":7,"title":["A novel zebrafish model for intermediate type spinal muscular atrophy demonstrates importance of Smn for maintenance of mature motor neurons"],"prefix":"10.1093","volume":"30","author":[{"given":"Shermaine Huiping","family":"Tay","sequence":"first","affiliation":[{"name":"Department of Biological Sciences, Centre for Bioimaging Sciences, National University of Singapore, Singapore 117543, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erna Nur","family":"Ellieyana","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, Centre for Bioimaging Sciences, National University of Singapore, Singapore 117543, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yao","family":"Le","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, Centre for Bioimaging Sciences, National University of Singapore, Singapore 117543, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Menachem Viktor","family":"Sarusie","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, Centre for Bioimaging Sciences, National University of Singapore, Singapore 117543, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clemens","family":"Grimm","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Biocenter, University of Wuerzburg, Wuerzburg 97074, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J\u00fcrgen","family":"Ohmer","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Biocenter, University of Wuerzburg, Wuerzburg 97074, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ajay S","family":"Mathuru","sequence":"additional","affiliation":[{"name":"Yale-NUS College, Singapore 138527, Singapore"},{"name":"Institute of Molecular and Cell Biology, Singapore 138673, Singapore"},{"name":"Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117593, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Utz","family":"Fischer","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Biocenter, University of Wuerzburg, Wuerzburg 97074, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4688-6241","authenticated-orcid":false,"given":"Christoph","family":"Winkler","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, Centre for Bioimaging Sciences, National University of Singapore, Singapore 117543, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2021,7,23]]},"reference":[{"key":"2021120506362079400_ref1","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1016\/0092-8674(95)90460-3","article-title":"Identification and characterization of a spinal muscular atrophy-determining gene","volume":"80","author":"Lefebvre","year":"1995","journal-title":"Cell"},{"key":"2021120506362079400_ref2","doi-asserted-by":"crossref","first-page":"615","DOI":"10.1016\/S0092-8674(00)81632-3","article-title":"A novel function for SMN, the spinal muscular atrophy disease gene product, in pre-mRNA splicing","volume":"95","author":"Pellizzoni","year":"1998","journal-title":"Cell"},{"key":"2021120506362079400_ref3","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1093\/hmg\/9.2.259","article-title":"An exonic enhancer is required for inclusion of an essential exon in the SMA-determining gene SMN","volume":"9","author":"Lorson","year":"2000","journal-title":"Hum. 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