| Evaluation of loss of function as an explanation for SPG4-based hereditary spastic paraplegia. | |
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MedLine Citation:
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PMID: 20430936 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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The spectrum of mutations (missense, non-sense and splice-site) associated with hereditary spastic paraplegia 4 (HSP-SPG4) (SPG4:OMIM#182601) has suggested that this autosomal dominant disease results from loss of function. Because the protein encoded by SPG4, termed spastin, is a microtubule-severing enzyme, a loss-of-function scenario for the disease suggests that corticospinal axons degenerate due to inadequate microtubule severing resulting from inactivation of one spastin allele. Lending more complexity to the situation, there are two major isoforms of spastin (M1 and M87) translated from two start codons. M87 is widely expressed, while M1 is appreciably detected only in adult spinal cord. Here, we focused on four HSP-associated mutations of the SPG4 gene located outside of the AAA region essential for microtubule severing. We found that none of these mutations affected the enzymatic activity or expression levels of either M1 or M87. Three of the mutations resulted in dominant-negative activity of M1. Surprisingly, the S44L mutation, which is asymptomatic when present heterozygously, conferred dominant-negative activity, while the E112K mutation, which is symptomatic when present heterozygously, did not. Clinical symptoms reported for patients carrying the dominant-negative mutations L195V or 46Stop are not more severe than those reported for patients carrying the non-dominant-negative E112K mutation. These results indicate that there are cases of HSP-SPG4 that cannot be explained by insufficient spastin microtubule-severing activity. |
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Authors:
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Joanna M Solowska; James Y Garbern; Peter W Baas |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S. Date: 2010-04-29 |
Journal Detail:
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Title: Human molecular genetics Volume: 19 ISSN: 1460-2083 ISO Abbreviation: Hum. Mol. Genet. Publication Date: 2010 Jul |
Date Detail:
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Created Date: 2010-06-30 Completed Date: 2010-09-28 Revised Date: 2011-08-01 |
Medline Journal Info:
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Nlm Unique ID: 9208958 Medline TA: Hum Mol Genet Country: England |
Other Details:
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Languages: eng Pagination: 2767-79 Citation Subset: IM |
Affiliation:
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Department of Neurobiology and Anatomy, Drexel University College of Medicine, 2900 Queen Lane, Philadelphia, PA 19129, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Adenosine Triphosphatases
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genetics*,
metabolism,
physiology* Base Sequence Cells, Cultured Genes, Dominant / physiology Humans Loss of Heterozygosity / physiology Microtubules / genetics, metabolism Models, Biological Mutation / physiology Protein Isoforms / genetics, metabolism, physiology Protein Multimerization / genetics Spastic Paraplegia, Hereditary / genetics* Transfection |
| Chemical | |
Reg. No./Substance:
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0/Protein Isoforms; EC 3.6.1.-/Adenosine Triphosphatases; EC 3.6.1.-/SPAST protein, human |
| Comments/Corrections | |
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