Not all SPG4 HSP the same

Insufficient spastin not the only cause

This study shows that there are cases of HSP-SPG4 that cannot be explained by insufficient spastin microtubule-severing activity.

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.

SOURCE: Hum Mol Genet. 2010 May 11.[Epub ahead of print]

Evaluation of loss of function as an explanation for SPG4-based hereditary spastic paraplegia.

Solowska JM, Garbern JY, Baas PW.

Department of Neurobiology and Anatomy, Drexel University College of Medicine, 2900 Queen Lane, Philadelphia, PA 19129, USA

1 comment

  1. Myself and my 20 year old twins all suffer from HSP. We are all affected differently.

    I’m a 53 year old woman and my walking has deteriorated significantly over the past two years.

    My son Andrew walks on the tips of the toes and trips constantly and he walks with an inward gait.

    My daughter Cody walked on her toes as child. Now 20 she experiences calf pain and trips over a lot. Unless you observe her closely you can’t tell she is affected from HSP.

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