Delving further into SPG4 mutations


Spastin oversupply linked to late onset HSP


Splice-site mutations are common in SPG4, causing skipping of exon 12 and affecting the amount of Spastin produced. It may be that a higher level of functional Spastin causes late onset HSP.



mutations in the SPG4/SPAST gene are the most common cause for hereditary spastic paraplegia (HSP). The splice-site mutations make a significant contribution to HSP and account for 17.4% of all types of mutations and 30.8% of point mutations in the SPAST gene. However, only few studies with limited molecular approach were conducted to investigate and decipher the role of SPAST splice-site mutations in HSP.


a reverse transcriptase-polymerase chain reaction (RT-PCR) analysis and quantitative allele-specific expression assay were performed.


we have characterized the consequence of two novel splice-site mutations (c.1493 + 1G>A and c.1414-1G>A) in the SPAST gene in two different families with pure HSP. The RT-PCR analysis revealed that both spastin mutations are indeed splice-site mutations and cause skipping of exon 12. Furthermore, RT-PCR data suggested that these splice-site mutations may cause leaky splicing. By means of a quantitative allele-specific expression assay, we could confirm that both splice-site mutations cause leaky splicing, as the relative expression of the exon 12-skipped transcript was reduced (21.1 ± 3.6 compared to expected 50%).


our finding supports a “threshold-effect-model” for functional spastin in HSP. A higher level (78.8 ± 3.9%) of functional spastin than the expected ratio of 50% owing to leaky splicing might cause late age at onset of HSP. Remarkably, we could show that a quantitative allele-specific expression assay is a simple and effective tool to evaluate the role of most types of spastin splice-site mutations in HSP.


SOURCE: Eur J Neurol. 2011 Jan;18(1):99-105.

Evaluating the effect of spastin splice mutations by quantitative allele-specific expression assay.


Klimpe S, Zibat A, Zechner U, Wellek B, Shoukier M, Sauter SM, Pantakani DV, Mannan AU.


Department of Neurology, University Medical Center, Johannes Gutenberg University, Mainz, Germany.


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