Taking into account previously published results and new data generated in this work, genetic studies revealed significant or putative linkage to known HSP loci in 13 families (34.2%) to either SPG11 (7/38, 18.4%), SPG15 (4/38, 10.5%) or to SPG4 and SPG5 in one family each.
This may suggest a different disease mechanism with more prominent axonal degeneration in these two types of HSP when compared with HSP due to spastin and atlastin mutations.
We studied in more detail the SPG5-related spectrum of complex phenotypes by screening CYPB1 for mutations in a large cohort of 105 Italian hereditary spastic paraplegias (HSPs) index patients including 50 patients with a complicated HSP (cHSP) phenotype overlapping the SPG11- and the SPG15-related forms except for the lack of thin corpus callosum and 55 pure patients.
The new SPG7 gene mutation leads to a novel complicated autosomal recessive hereditary spastic paraparesis phenotype that widens the spectrum of different brain systems that are optionally affected in hereditary spastic paraplegia (HSP).
The provided genomic structure of SPG7 should facilitate the screening for mutations in this gene in patients with HSP and other related mitochondrial disease syndromes.
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.
<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.
Using spastic paraplegia type 4 (SPG4, the most frequent HSP subtype) as an exemplar, we here present three rapid phenotypic assays for uncovering neuronal process pathologies in iPSC-derived glutamatergic cortical neurons.
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.