Spastin gene mutations in Bulgarian patients with hereditary spastic paraplegia

Abstract

Hereditary spastic paraplegia (HSP) is an extremely heterogeneous group of neurodegenerative disorders affecting the longest axons in the central nervous system. The most common genetic form accounting for about 40% of the autosomal-dominant HSP (ADHSP) cases is spastin gene, SPG4. We performed mutation screening of the spastin gene on 36 unrelated HSP patients from three different ethnic groups (Bulgarian, Turks and Gypsies) and found four new mutations and one already reported. The phenotype-genotype correlations in Bulgarian SPG4 patients showed a great difference in the age at disease onset between patients with missense mutations and those harboring deletions and splice-site mutations. Our study is the first to present corroborative clinical data in favor of the general hypothesis that the clinical course of the disease is related to the type of the spastin mutation. The clinical and genealogical findings in Bulgarian SPG4 patients suggest that a positive family history for inheritance as an autosomal-dominant trait is a strong indication for spastin mutation screening.

Expansion of mutation spectrum, determination of mutation cluster regions and predictive structural classification of SPAST mutations in hereditary spastic paraplegia

“…Previously, early AAO in patients with missense mutation was also reported; however, this study only accounted for two missense mutations out of a total five mutations. 40 Moreover, in a meta-analysis 38 no significant correlation between AAO and mutational class was evident, but one limitation of this study was the sample size. Nevertheless, these different pathomechanism modes, such as loss of function and dominant-negative function for different classes/types of spastin mutations need to be carefully resolved by experimental means; otherwise there will be repercussions on the likely success of any therapeutical approach devised for spastin-associated HSP.…”

ExonImpact: Prioritizing Pathogenic Alternative Splicing Events

“…Taking the SPAST (spastin) gene as an example (Fig. B), in the HGMD database, the mutation at chr2:32339706 locus is listed as altering the regulation of splicing of the fifth exon (NM_014946:227:290), and leads to a disease called spastic paraplegia [Ivanova et al., ]. According to UniProtKB (Uniprot ID: Q9UBP0,NM_014946), this region of the protein encodes a random coil structure, and serves as an interaction site with microtubules.…”

Autosomal Dominant Spastic Paraplegias

“…Association of mutational class of each gene with any phenotypic trait has never been possible, 3,4,33,[49][50][51] with the exception of a possible earlier disease onset in SPG4 mis- Abbreviation: ROM, range of movement. a Motor severity scale scores: 0 = normal; 1 = no functional handicap but signs at examination; 2 = mild, able to run, walking unlimited; 3 = moderate, unable to run, limited walking without aid; 4 = severe, walking with 1 stick; 5 = walking with 2 sticks; 6 = unable to walk, requiring wheelchair; 7 = confined to bed.…”