¹Institute of Human Genetics, University of Goettingen, Goettingen, Germany

Correspondence: Dr AU Mannan, Institute of Human Genetics, University of Goettingen, Heinrich-Dueker-Weg 12, D-37073, Goettingen, Germany. Tel: +49 551 397522; Fax +49 551 399303; E-mail: amannan@gwdg.de

²These authors contributed equally to this work

³Current address: Department of Medical Genetics, Medical University of Vienna, Vienna, Austria

Received 15 January 2008; Revised 9 July 2008; Accepted 11 July 2008; Published online 13 August 2008.

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.