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

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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.

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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.

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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.

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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)

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