One form of autosomal recessive HSP (on chromosome 16) is due to mutations in the paraplegin gene, which encodes a mitochondrial protein homologous to metalloproteases.
These data suggest that spastin and atlastin function in the same biochemical pathway and that it is the cytoplasmic function of spastin which is important for the pathogenesis of HSP.
By comparing the phenotypes and the complementation behaviors of a large set of Khc missense alleles, including one that is identical to a human Kif5AHSP allele, we identified three routes to suppression of Khc phenotypes: nutrient restriction, genetic background manipulation, and a remarkable intramolecular complementation between mutations known or likely to cause reciprocal changes in the rate of microtubule-stimulated ADP release by kinesin-1.
Mutations spread across atlastin isoform 1 (atlastin-1) have been identified in patients suffering from hereditary spastic paraplegia (HSP), a neurodegenerative disorder affecting motor neuron function in the lower extremities.
Inheritance of HSP is commonly autosomal dominant, spastin was identified as the defective gene in chromosome 2p-linked autosomal dominant hereditary spastic paraplegia (AD-HSP).
These data suggest that spastin and atlastin function in the same biochemical pathway and that it is the cytoplasmic function of spastin which is important for the pathogenesis of HSP.
<b>Results:</b> Fifty four patients with genetically confirmed HSP diagnosis, 36 with spastic paraplegia type 4 (SPG4), 5 SPG11, 4 SPG5, 4 cerebrotendinous xanthomatosis (CTX), 3 SPG7 and 2 SPG3A, and 10 healthy, unrelated control subjects, with similar age, sex, and education participated in the study.
We performed PCR-based direct sequencing of SPG4, followed by a linkage analysis and subsequent Southern blot analysis in large Japanese kindred where 20 of 33 members were evaluated neurologically, and consequently 6 were affected with HSP.
Overall, the comparison of the clinical data for all SPG3A-HSP families reported to date failed to reveal any genotype/phenotype correlation as demonstrated for other forms of AD-HSP.
Our results add to a growing number of HSP disease-associated variants and confirm the high prevalence of atlastin, spastin, and REEP1 mutations in the HSP patient population.
Experiments presented here using isolated squid axoplasm reveal inhibition of FAT as a common toxic effect elicited by spastin proteins with different HSP mutations, independent of microtubule-binding or severing activity.
The overall odds ratios (ORs) for the three loci were significant for HSP: HLA-DRB1 01 (OR = 1.805, 95 % CI 1.259-2.588, p = 0.0012); HLA-DRB1 07 (OR = 0.671, 95 % CI 0.469-0.961, p = 0.058); HLA-DRB1 11 (OR = 2.001, 95 % CI 1.50-2.67, p = 0.027).
A molecular diagnosis was obtained in 82.1 % of the cases (52 cases with mutations in SPAST/SPG4, two in SPG7, and one in SPG11).The prevalence of HSP among Sardinians is high compared with other Western European populations.
Our results show that SPG4 mutations and deletions are a significant cause of HSP in our population and warrant SPG4 screening in AD families and selected sporadic cases.