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. 2009 Feb;17(2):187-94.
doi: 10.1038/ejhg.2008.147. Epub 2008 Aug 13.

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

Moneef Shoukier  1 , Juergen Neesen, Simone M Sauter, Loukas Argyriou, Nadine Doerwald, D V Krishna Pantakani, Ashraf U Mannan
Affiliations

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

Moneef Shoukier et al. Eur J Hum Genet. 2009 Feb.

Erratum in

  • Eur J Hum Genet. 2009 Mar;17(3):401-2

Abstract

The SPAST gene encoding for spastin plays a central role in the genetically heterogeneous group of diseases termed hereditary spastic paraplegia (HSP). In this study, we attempted to expand and refine the genetic and phenotypic characteristics of SPAST associated HSP by examining a large cohort of HSP patients/families. Screening of 200 unrelated HSP cases for mutations in the SPAST gene led to detection of 57 mutations (28.5%), of which 47 were distinct and 29 were novel mutations. The distribution analysis of known SPAST mutations over the structural domains of spastin led to the identification of several regions where the mutations were clustered. Mainly, the clustering was observed in the AAA (ATPases associated with diverse cellular activities) domain; however, significant clustering was also observed in the MIT (microtubule interacting and trafficking), MTBD (microtubule-binding domain) and an N-terminal region (228-269 residues). Furthermore, we used a previously generated structural model of spastin as a framework to classify the missense mutations in the AAA domain from the HSP patients into different structural/functional groups. Our data also suggest a tentative genotype-phenotype correlation and indicate that the missense mutations could cause an earlier onset of the disease.

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Figures

Figure 1
Figure 1
Schematic diagram representing the structural domains of the spastin protein (616 amino acids) and showing the localization of the identified mutations. The different domains are highlighted with different colors and different kinds of mutations are marked with different symbols as summarized on the left at the bottom of the figure. (a) Representation of 26 novel mutations identified in our study. Twenty-two out of 26 mutations are located in the AAA domain and two others in the MIT domain. (b) Distribution of all mutations identified to date in the spastin protein. The primary hot spot region is indicated as a red bar in the AAA domain. Three secondary hot spot regions are shown as orange bars below the spastin structure. Note: Three novel gross deletions are not included for representation; also gross deletions are excluded for distribution analysis.
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