Mutations in SPG11, encoding spatacsin, are a major cause of spastic paraplegia with thin corpus callosum

Article metrics


Autosomal recessive hereditary spastic paraplegia (ARHSP) with thin corpus callosum (TCC) is a common and clinically distinct form of familial spastic paraplegia that is linked to the SPG11 locus on chromosome 15 in most affected families. We analyzed 12 ARHSP-TCC families, refined the SPG11 candidate interval and identified ten mutations in a previously unidentified gene expressed ubiquitously in the nervous system but most prominently in the cerebellum, cerebral cortex, hippocampus and pineal gland. The mutations were either nonsense or insertions and deletions leading to a frameshift, suggesting a loss-of-function mechanism. The identification of the function of the gene will provide insight into the mechanisms leading to the degeneration of the corticospinal tract and other brain structures in this frequent form of ARHSP.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: Critical region of SPG11.
Figure 2: Pedigrees and segregation of the mutations detected in KIAA1840.
Figure 3: Expression profile of KIAA1840 examined by RNA blot in human adult brain.
Figure 4: Spatial expression of rat KIAA1840 in adult brain (P68) by in situ hybridization with a pool of three antisense probes or a pool of three sense probes.

Accession codes




  1. 1

    Harding, A.E. Classification of the hereditary ataxias and paraplegias. Lancet 1, 1151–1155 (1983).

  2. 2

    Nakamura, A. et al. Familial spastic paraplegia with mental impairment and thin corpus callosum. J. Neurol. Sci. 131, 35–42 (1995).

  3. 3

    Winner, B. et al. Clinical progression and genetic analysis in hereditary spastic paraplegia with thin corpus callosum in spastic gait gene 11 (SPG11). Arch. Neurol. 61, 117–121 (2004).

  4. 4

    Martinez, M.F. et al. Genetic localization of a new locus for recessive familial spastic paraparesis to 15q13–15. Neurology 53, 50–56 (1999).

  5. 5

    Casali, C. et al. Clinical and genetic studies in hereditary spastic paraplegia with thin corpus callosum. Neurology 62, 262–268 (2004).

  6. 6

    Shibasaki, Y. et al. Linkage of autosomal recessive hereditary spastic paraplegia with mental impairment and thin corpus callosum to chromosome 15q13–15. Ann. Neurol. 48, 108–112 (2000).

  7. 7

    Lossos, A. et al. Hereditary spastic paraplegia with thin corpus callosum: reduction of the SPG11 interval and evidence for further genetic heterogeneity. Arch. Neurol. 63, 756–760 (2006).

  8. 8

    Stevanin, G. et al. Spastic paraplegia with thin corpus callosum: description of 20 new families, refinement of the SPG11 locus, candidate gene analysis and evidence of genetic heterogeneity. Neurogenetics 7, 149–156 (2006).

  9. 9

    Olmez, A. et al. Further clinical and genetic characterization of SPG11: hereditary spastic paraplegia with thin corpus callosum. Neuropediatrics 37, 59–66 (2006).

  10. 10

    Orlacchio, A. et al. Clinical and genetic study of a large SPG4 Italian family. Mov. Disord. 20, 1055–1059 (2005).

  11. 11

    Hughes, C.A. et al. SPG15, a new locus for autosomal recessive complicated HSP on chromosome 14q. Neurology 56, 1230–1233 (2001).

  12. 12

    Simpson, M.A. et al. Maspardin is mutated in mast syndrome, a complicated form of hereditary spastic paraplegia associated with dementia. Am. J. Hum. Genet. 73, 1147–1156 (2003).

  13. 13

    Al Yahyaee, S. et al. A novel locus for hereditary spastic paraplegia with thin corpus callosum and epilepsy. Neurology 66, 1230–1234 (2006).

  14. 14

    Howard, H.C. et al. The K-Cl cotransporter KCC3 is mutant in a severe peripheral neuropathy associated with agenesis of the corpus callosum. Nat. Genet. 32, 384–392 (2002).

  15. 15

    Callebaut, I. et al. Deciphering protein sequence information through hydrophobic cluster analysis (HCA): current status and perspectives. Cell. Mol. Life Sci. 53, 621–645 (1997).

  16. 16

    Nagase, T., Nakayama, M., Nakajima, D., Kikuno, R. & Ohara, O. Prediction of the coding sequences of unidentified human genes. XX. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro. DNA Res. 8, 85–95 (2001).

  17. 17

    Paisan-Ruiz, C. et al. Cloning of the gene containing mutations that cause PARK8-linked Parkinson's disease. Neuron 44, 595–600 (2004).

  18. 18

    Crosby, A.H. & Proukakis, C. Is the transportation highway the right road for hereditary spastic paraplegia? Am. J. Hum. Genet. 71, 1009–1016 (2002).

  19. 19

    Gudbjartsson, D.F., Jonasson, K., Frigge, M.L. & Kong, A. Allegro, a new computer program for multipoint linkage analysis. Nat. Genet. 25, 12–13 (2000).

  20. 20

    Elleuch, N. et al. Mutation analysis of the paraplegin gene (SPG7) in patients with hereditary spastic paraplegia. Neurology 66, 654–659 (2006).

  21. 21

    Moutsimilli, L. et al. Selective cortical VGLUT1 increase as a marker for antidepressant activity. Neuropharmacology 49, 890–900 (2005).

  22. 22

    Woodcock, S., Mornon, J.P. & Henrissat, B. Detection of secondary structure elements in proteins by hydrophobic cluster analysis. Protein Eng. 5, 629–635 (1992).

  23. 23

    Mucchielli-Giorgi, M.H., Hazout, S. & Tuffery, P. Predicting the disulfide bonding state of cysteines using protein descriptors. Proteins 46, 243–249 (2002).

  24. 24

    Kikuno, R., Nagase, T., Waki, M. & Ohara, O. HUGE: a database for human large proteins identified in the Kazusa cDNA sequencing project. Nucleic Acids Res. 30, 166–168 (2002).

Download references


Most of the families were examined and sampled by neurologists participating in SPATAX (the European Network for Hereditary Spinocerebellar Degenerative Disorders). The authors wish to thank the family members for their participation as well as F. Durand-Dubief, C. Tallaksen, P. Ribai and SPATAX members for referring or examining several of the patients. We are also indebted to O. Corti, C. Depienne and S. Dumas for helpful discussions; N. Barton for critical reading of the manuscript and S. Forlani, I. Lagroua, L. Guennec, P. Ibanez, E. Denis and N. Benammar for their assistance. We also thank the DNA Bank of IFR-70 and the Brain Bank of INSERM U679 (E. Hirsch) for providing us with biological material and the Centre National de Génotypage for the genome scan in family FSP221. The pf01011 clone containing the KIAA1840 full-length cDNA was provided by the Kazusa DNA Research Institute. This work was supported financially by grants from the French Rare Diseases Institute (to G.S. and A.D.), the Verum Foundation (to A.B.), the Italian Ministry of Health (to F.M.S. and E.B.), the Pierfranco and Luisa Mariani Foundation ONLUS (to F.M.S.), Telethon-Italia Foundation (grant number GGP06188 to F.M.S.), the association Strümpell-Lorrain (to the SPATAX network), the Portuguese Foundation for Science and Technology (to P.C., J.L.L. and V.T.C.) and the French National Agency for Research (to the SPATAX network). N.B. and N.E. received fellowships from the French Association for Friedreich Ataxia and the French association Connaître les Syndromes Cérébelleux, P.S.D. is a fellow of The Bambino Gesù Research Program and H.A. was the recipient of a fellowship from the French Association Against Myopathies.

Author information

Clinical data were acquired by F.M.S. P.C., A.M.O.H., A.L., P.C., J.L.L., C.C., V.T.C., D.G., M.T., B.F., A.F., E.B., E.L., A.D. and A.B.; F.M.S., N.B., A.T. and G.S. refined the candidate interval using additional markers and families. H.A., F.M.S., N.E., P.S.D. and G.S. analyzed the candidate genes and identified the mutations. E.M. and P.S.D. performed the overexpression studies. F.M.S., P.S.D. and G.S. analyzed the expression of the gene. Bioinformatics studies were performed by H.A., J.C. and G.S.; H.A., F.M.S., A.B., A.D., M.R. and G.S. wrote the paper. A.B., F.M.S. and G.S. supervised the work. Funding was obtained by A.B., F.M.S., E.B., P.C., A.D. and G.S.

Correspondence to Giovanni Stevanin.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

Multipoint linkage analysis performed in ten informative families for 34 microsatellite markers from chromosome 15q. (PDF 78 kb)

Supplementary Fig. 2

Pedigrees of two SPG11 families that reduced the candidate interval. (PDF 74 kb)

Supplementary Fig. 3

Internal structural duplication in spatacsin. (PDF 106 kb)

Supplementary Fig. 4

Expression of the spatacsin-EGFP fusion protein in COS-7 cells 48 h after transfection. (PDF 455 kb)

Supplementary Fig. 5

In situ hybridization in adult rat. (PDF 205 kb)

Supplementary Fig. 6

Specificity of the in situ hybridization of KIAA1840 probes in adult rat. (PDF 752 kb)

Supplementary Table 1

Primers used. (PDF 28 kb)

Supplementary Note

Clinical data and bioethics. (PDF 20 kb)

Rights and permissions

Reprints and Permissions

About this article

Further reading