title: Expansion of mutation spectrum, determination of mutation cluster regions and predictive structural classification of SPAST mutations in hereditary spastic paraplegia.
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.
authors.affiliation: Institute of Human Genetics, University of Goettingen, Goettingen, Germany.
authors.forename: Moneef
authors.initials: M
authors.lastname: Shoukier
authors.forename: Juergen
authors.initials: J
authors.lastname: Neesen
authors.forename: Simone M
authors.initials: SM
authors.lastname: Sauter
authors.forename: Loukas
authors.initials: L
authors.lastname: Argyriou
authors.forename: Nadine
authors.initials: N
authors.lastname: Doerwald
authors.forename: D V Krishna
authors.initials: DV
authors.lastname: Pantakani
authors.forename: Ashraf U
authors.initials: AU
authors.lastname: Mannan
mesh_terms: D000251:Adenosine Triphosphatases / Q000235:genetics*; D017668:Age of Onset; D004252:DNA Mutational Analysis; D006801:Humans; D020125:Mutation, Missense; D015419:Spastic Paraplegia, Hereditary / Q000453:epidemiology / Q000235:genetics* / Q000503:physiopathology; D000074181:Spastin
chemical_list: D000251:Adenosine Triphosphatases; D000074181:Spastin; C400283:SPAST protein, human