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https://doi.org/10.1093/hmg/ddab212
Title: | A novel zebrafish model for intermediate type spinal muscular atrophy demonstrates importance of Smn for maintenance of mature motor neurons | Authors: | Tay, Shermaine Huiping Ellieyana, Erna Nur Le, Yao Sarusie, Menachem Viktor Grimm, Clemens Ohmer, Jurgen Mathuru, Ajay S Fischer, Utz Winkler, Christoph |
Keywords: | Science & Technology Life Sciences & Biomedicine Biochemistry & Molecular Biology Genetics & Heredity NEUROMUSCULAR-JUNCTION MOUSE MODEL EMBRYONIC-DEVELOPMENT SINGLE NUCLEOTIDE ANIMAL-MODEL GENE SURVIVAL PROTEIN DEFECTS MICE |
Issue Date: | 23-Jul-2021 | Publisher: | OXFORD UNIV PRESS | Citation: | Tay, Shermaine Huiping, Ellieyana, Erna Nur, Le, Yao, Sarusie, Menachem Viktor, Grimm, Clemens, Ohmer, Jurgen, Mathuru, Ajay S, Fischer, Utz, Winkler, Christoph (2021-07-23). A novel zebrafish model for intermediate type spinal muscular atrophy demonstrates importance of Smn for maintenance of mature motor neurons. HUMAN MOLECULAR GENETICS 30 (24) : 2488-2502. ScholarBank@NUS Repository. https://doi.org/10.1093/hmg/ddab212 | Abstract: | 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 1-4) 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 days. 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. | Source Title: | HUMAN MOLECULAR GENETICS | URI: | https://scholarbank.nus.edu.sg/handle/10635/217960 | ISSN: | 0964-6906 1460-2083 |
DOI: | 10.1093/hmg/ddab212 |
Appears in Collections: | Staff Publications Elements |
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Tay et al HMG 2021.pdf | Published version | 2.22 MB | Adobe PDF | OPEN | Published | View/Download |
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