Journal article
Evaluation of loss of function as an explanation for SPG4-based hereditary spastic paraplegia
Human molecular genetics, Vol.19(14), pp.2767-2779
15 Jul 2010
PMCID: PMC2893808
PMID: 20430936
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
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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Details
- Title
- Evaluation of loss of function as an explanation for SPG4-based hereditary spastic paraplegia
- Creators
- Joanna M Solowska - Drexel University College of MedicineJames Y Garbern - Wayne State University School of MedicinePeter W Baas - Drexel University College of Medicine
- Publication Details
- Human molecular genetics, Vol.19(14), pp.2767-2779
- Publisher
- Oxford University Press
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Neurobiology and Anatomy
- Identifiers
- 991014878332604721
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