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.

WASH and WAVE actin regulators of the Wiskott–Aldrich syndrome protein (WASP) family are controlled by analogous structurally related complexes

“…S8C). Finally, given the association of Strumpellin with HSP (15), and the fact that the known mutations do not affect SHRC assembly, it will be important to examine the effect of these mutations on the cellular and biochemical activities of the SHRC.…”

“…Strumpellin has no identifiable subdomains, but the protein is predicted to be highly helical. The gene encoding Strumpellin was recently found mutated in the neurodegenerative disease hereditary spastic paraplegia (HSP), but there is no understanding of Strumpellin function or how its mutations give rise to disease (14,15). Finally, no functions have been reported for SWIP, which like Strumpellin has no recognizable subdomains and is predicted to be highly helical.…”

“…Several of the genes mutated in HSP, an autosomal dominant disease characterized by progressive motor neuron loss, are known to participate in endosomal trafficking or microtubule dynamics (14). Because WASH functions to regulate endosomal sorting, it is interesting that three distinct HSP-associated point mutations were recently described within the SHRC component, Strumpellin (15). Thus, we were interested in determining the assembly of Strumpellin into the SHRC as well as the consequence of HSPassociated Strumpellin mutations on SHRC assembly.…”

Cellular functions of WASP family proteins at a glance

“…In contrast, genetic deletion of WASH in mice results in early embryonic lethality Xia et al, 2013). Interestingly, mutations in the genes encoding KIAA1033 and strumpellin have been linked to intellectual disability (ID) syndromes (Elliott et al, 2013;Ropers et al, 2011), and separate mutations in strumpellin have been found in patients with hereditary spastic paraplegia (HSP) (Valdmanis et al, 2007). However, the mechanism by which WASH deregulation contributes to the pathology of either disease is unclear.…”

Clinical features and management of hereditary spastic paraplegia

“…Mutations in the SPG 6 15 and SPG 8 16 are pure HSPs that have already been identified in the Brazilian population. SPG 6 presents as a slowly progressive, mostly pure spastic paraplegia in early-adulthood 15 (Table 1).…”