Please use this identifier to cite or link to this item: 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
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