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Transcriptional and post-transcriptional regulation of spast, the gene most frequently mutated in hereditary spastic paraplegia

Henson, BJ and Zhu, W and Hardaway, K and Wetzel, JL and Stefan, M and Albers, KM and Nicholls, RD (2012) Transcriptional and post-transcriptional regulation of spast, the gene most frequently mutated in hereditary spastic paraplegia. PLoS ONE, 7 (5).

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Hereditary spastic paraplegias (HSPs) comprise a group of neurodegenerative disorders that are characterized by progressive spasticity of the lower extremities, due to axonal degeneration in the corticospinal motor tracts. HSPs are genetically heterogeneous and show autosomal dominant inheritance in ~70-80% of cases, with additional cases being recessive or X-linked. The most common type of HSP is SPG4 with mutations in the SPAST gene, encoding spastin, which occurs in 40% of dominantly inherited cases and in ~10% of sporadic cases. Both loss-of-function and dominant-negative mutation mechanisms have been described for SPG4, suggesting that precise or stoichiometric levels of spastin are necessary for biological function. Therefore, we hypothesized that regulatory mechanisms controlling expression of SPAST are important determinants of spastin biology, and if altered, could contribute to the development and progression of the disease. To examine the transcriptional and post-transcriptional regulation of SPAST, we used molecular phylogenetic methods to identify conserved sequences for putative transcription factor binding sites and miRNA targeting motifs in the SPAST promoter and 3′-UTR, respectively. By a variety of molecular methods, we demonstrate that SPAST transcription is positively regulated by NRF1 and SOX11. Furthermore, we show that miR-96 and miR-182 negatively regulate SPAST by effects on mRNA stability and protein level. These transcriptional and miRNA regulatory mechanisms provide new functional targets for mutation screening and therapeutic targeting in HSP. © 2012 Henson et al.


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Item Type: Article
Status: Published
CreatorsEmailPitt UsernameORCID
Henson, BJ
Zhu, W
Hardaway, K
Wetzel, JL
Stefan, M
Albers, KMkaa2@pitt.eduKAA2
Nicholls, RDrdn4@pitt.eduRDN4
ContributionContributors NameEmailPitt UsernameORCID
Date: 4 May 2012
Date Type: Publication
Journal or Publication Title: PLoS ONE
Volume: 7
Number: 5
DOI or Unique Handle: 10.1371/journal.pone.0036505
Schools and Programs: School of Public Health > Human Genetics
Refereed: Yes
MeSH Headings: 3' Untranslated Regions--genetics; Adenosine Triphosphatases--genetics; Animals; Base Sequence; Cell Line; Conserved Sequence--genetics; Gene Expression Regulation; Genetic Loci--genetics; Humans; MicroRNAs--genetics; MicroRNAs--metabolism; Molecular Sequence Data; Mutation Rate; Nuclear Respiratory Factor 1--metabolism; Nucleotide Motifs--genetics; Paraplegia--diagnosis; Paraplegia--enzymology; Paraplegia--genetics; Paraplegia--therapy; Primates--genetics; Promoter Regions, Genetic--genetics; Proprotein Convertases--metabolism; SOXC Transcription Factors--metabolism; Serine Endopeptidases--metabolism; Transcription, Genetic
Other ID: NLM PMC3344893
PubMed Central ID: PMC3344893
PubMed ID: 22574173
Date Deposited: 04 Oct 2012 14:10
Last Modified: 27 May 2019 13:55


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