title: Mutations in the KIAA0196 gene at the SPG8 locus cause hereditary spastic paraplegia.
abstract: Hereditary spastic paraplegia (HSP) is a progressive upper-motor neurodegenerative disease. The eighth HSP locus, SPG8, is on chromosome 8p24.13. The three families previously linked to the SPG8 locus present with relatively severe, pure spastic paraplegia. We have identified three mutations in the KIAA0196 gene in six families that map to the SPG8 locus. One mutation, V626F, segregated in three large North American families with European ancestry and in one British family. An L619F mutation was found in a Brazilian family. The third mutation, N471D, was identified in a smaller family of European origin and lies in a spectrin domain. None of these mutations were identified in 500 control individuals. Both the L619 and V626 residues are strictly conserved across species and likely have a notable effect on the structure of the protein product strumpellin. Rescue studies with human mRNA injected in zebrafish treated with morpholino oligonucleotides to knock down the endogenous protein showed that mutations at these two residues impaired the normal function of the KIAA0196 gene. However, the function of the 1,159-aa strumpellin protein is relatively unknown. The identification and characterization of the KIAA0196 gene will enable further insight into the pathogenesis of HSP.
authors.affiliation: Hopital Notre-Dame-CHUM, Montreal, Quebec, H2L 4M1, Canada.
authors.forename: Paul N
authors.initials: PN
authors.lastname: Valdmanis
authors.forename: Inge A
authors.initials: IA
authors.lastname: Meijer
authors.forename: Annie
authors.initials: A
authors.lastname: Reynolds
authors.forename: Adrienne
authors.initials: A
authors.lastname: Lei
authors.forename: Patrick
authors.initials: P
authors.lastname: MacLeod
authors.forename: David
authors.initials: D
authors.lastname: Schlesinger
authors.forename: Mayana
authors.initials: M
authors.lastname: Zatz
authors.forename: Evan
authors.initials: E
authors.lastname: Reid
authors.forename: Patrick A
authors.initials: PA
authors.lastname: Dion
authors.forename: Pierre
authors.initials: P
authors.lastname: Drapeau
authors.forename: Guy A
authors.initials: GA
authors.lastname: Rouleau
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002898:Chromosomes, Human, Pair 8 / Q000235:genetics; D005796:Genes; D020022:Genetic Predisposition to Disease; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D011506:Proteins / Q000235:genetics*; D017386:Sequence Homology, Amino Acid; D015419:Spastic Paraplegia, Hereditary / Q000235:genetics*; D013116:Spinal Cord / Q000002:abnormalities; D015027:Zebrafish / Q000002:abnormalities / Q000235:genetics / Q000378:metabolism
chemical_list: D011506:Proteins; C517003:WASHC5 protein, human