PUBLICATION

Mutations in the KIAA0196 Gene at the SPG8 Locus Cause Hereditary Spastic Paraplegia

Authors
Valdmanis, P.N., Meijer, I.A., Reynolds, A., Lei, A., Macleod, P., Schlesinger, D., Zatz, M.,. Reid, E., Dion, P.A., Drapeau, P., and Rouleau, G.A.
ID
ZDB-PUB-061227-37
Date
2007
Source
American journal of human genetics   80(1): 152-161 (Journal)
Registered Authors
Drapeau, Pierre
Keywords
none
MeSH Terms
  • Amino Acid Sequence
  • Animals
  • Chromosomes, Human, Pair 8/genetics
  • Genes*
  • Genetic Predisposition to Disease*
  • Humans
  • Models, Molecular
  • Molecular Sequence Data
  • Mutation
  • Pedigree*
  • Proteins/genetics*
  • Sequence Homology, Amino Acid
  • Spastic Paraplegia, Hereditary/genetics*
  • Spinal Cord/abnormalities
  • Zebrafish/abnormalities
  • Zebrafish/genetics
  • Zebrafish/metabolism
PubMed
17160902 Full text @ Am. J. Hum. Genet.
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.
Genes / Markers
Figures
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Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping