Southgate, L;
Dafou, D;
Hoyle, J;
Li, N;
Kinning, E;
Critchley, P;
Németh, AH;
Talbot, K;
Bindu, PS;
Sinha, S;
et al.
Southgate, L; Dafou, D; Hoyle, J; Li, N; Kinning, E; Critchley, P; Németh, AH; Talbot, K; Bindu, PS; Sinha, S; Taly, AB; Raghavendra, S; Müller, F; Maher, ER; Trembath, RC
(2010)
Novel SPG11 mutations in Asian kindreds and disruption of spatacsin function in the zebrafish.
Neurogenetics, 11 (4).
pp. 379-389.
ISSN 1364-6753
https://doi.org/10.1007/s10048-010-0243-8
SGUL Authors: Southgate, Laura
Abstract
Autosomal recessive hereditary spastic paraplegia with thin corpus callosum (HSP-TCC) maps to the SPG11 locus in the majority of cases. Mutations in the KIAA1840 gene, encoding spatacsin, have been shown to underlie SPG11-linked HSP-TCC. The aim of this study was to perform candidate gene analysis in HSP-TCC subjects from Asian families and to characterize disruption of spatacsin function during zebrafish development. Homozygosity mapping and direct sequencing were used to assess the ACCPN, SPG11, and SPG21 loci in four inbred kindreds originating from the Indian subcontinent. Four novel homozygous SPG11 mutations (c.442+1G>A, c.2146C>T, c.3602_3603delAT, and c.4846C>T) were identified, predicting a loss of spatacsin function in each case. To investigate the role of spatacsin during development, we additionally ascertained the complete zebrafish spg11 ortholog by reverse transcriptase PCR and 5′ RACE. Analysis of transcript expression through whole-mount in situ hybridization demonstrated ubiquitous distribution, with highest levels detected in the brain. Morpholino antisense oligonucleotide injection was used to knock down spatacsin function in zebrafish embryos. Examination of spg11 morphant embryos revealed a range of developmental defects and CNS abnormalities, and analysis of axon pathway formation demonstrated an overall perturbation of neuronal differentiation. These data confirm loss of spatacsin as the cause of SPG11-linked HSP-TCC in Asian kindreds, expanding the mutation spectrum recognized in this disorder. This study represents the first investigation in zebrafish addressing the function of a causative gene in autosomal recessive HSP and identifies a critical role for spatacsin during early neural development in vivo.
Item Type: |
Article
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Additional Information: |
© The Author(s) 2010
Open Access
This is an open access article distributed under the terms of the Creative Commons Attribution Noncommercial License (https://creativecommons.org/licenses/by-nc/2.0), which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited. |
Keywords: |
Adaptor Proteins, Signal Transducing, Adolescent, Adult, Amino Acid Sequence, Animals, Asian Continental Ancestry Group, Carrier Proteins, Female, Humans, India, Male, Microsatellite Repeats, Molecular Sequence Data, Mutation, Proteins, Sequence Homology, Amino Acid, Zebrafish, Animals, Zebrafish, Humans, Adaptor Proteins, Signal Transducing, Proteins, Carrier Proteins, Amino Acid Sequence, Microsatellite Repeats, Sequence Homology, Amino Acid, Mutation, Molecular Sequence Data, Adolescent, Adult, Asian Continental Ancestry Group, India, Female, Male, Hereditary spastic paraplegia, SPG11, Molecular genetics, Zebrafish studies, 0604 Genetics, 1109 Neurosciences, 1702 Cognitive Science, Neurology & Neurosurgery |
Journal or Publication Title: |
Neurogenetics |
ISSN: |
1364-6753 |
Language: |
eng |
Dates: |
Date | Event |
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October 2010 | Published | 14 April 2010 | Published Online | 16 March 2010 | Accepted |
|
Publisher License: |
Creative Commons: Attribution-Noncommercial 2.0 |
Projects: |
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PubMed ID: |
20390432 |
Web of Science ID: |
WOS:000282183200002 |
![](http://static.pubmed.gov/portal/portal3rc.fcgi/2745237/img/27842) |
Go to PubMed abstract |
URI: |
https://openaccess.sgul.ac.uk/id/eprint/111364 |
Publisher's version: |
https://doi.org/10.1007/s10048-010-0243-8 |
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