Point mutations and a large intragenic deletion in SPG11 in complicated spastic paraplegia without thin corpus callosum
- C Crimella1,
- A Arnoldi1,
- F Crippa1,
- M L Mostacciuolo2,
- F Boaretto2,
- M Sironi3,
- M Grazia D’Angelo4,
- S Manzoni4,
- L Piccinini4,
- A C Turconi4,
- A Toscano5,
- O Musumeci5,
- S Benedetti6,
- R Fazio7,
- N Bresolin1,8,
- A Daga9,
- A Martinuzzi10,
- M T Bassi1
- 1Scientific Institute E. Medea, Laboratory of Molecular Biology, Bosisio Parini, Italy
- 2Department of Biology, University of Padova, Italy
- 3Scientific Institute E. Medea Laboratory of Bioinformatics, Bosisio Parini, Italy
- 4Scientific Institute E. Medea, Neuromuscular and Neurorehabilitation Unit, Bosisio Parini, Italy
- 5Department of Neurosciences, Psychiatry and Anaesthesiology, University of Messina, Messina, Italy
- 6Laboratory of Clinical Molecular Biology, Diagnostica e Ricerca San Raffaele, Milan, Italy
- 7Department of Neurology, and Institute of Experimental Neurology (INSpe), San Raffaele Scientific Institute, Milan, Italy
- 8Dino Ferrari Centre, IRCCS Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena Foundation, Department of Neurological Sciences University of Milan, Italy
- 9Dulbecco Telethon Institute at the “E Medea” Scientific Institute, Conegliano Research Center, Conegliano, Italy
- 10Scientific Institute E. Medea, Conegliano Research Center, Conegliano, Italy
- Dr M T Bassi, Laboratory of Molecular Biology, E. Medea Scientific Institute, Via D. L. Monza 20, 23842 Bosisio Parini, Lecco, Italy; mariateresa.bassi{at}bp.lnf.it
- Received 17 September 2008
- Revised 28 November 2008
- Accepted 24 December 2008
- Published Online First 5 February 2009
Abstract
Background: Hereditary spastic paraplegia (HSP) with thin corpus callosum (HSP-TCC) is a frequent subtype of complicated HSP clinically characterised by slowly progressive spastic paraparesis with cognitive impairment and thin corpus callosum (TCC). SPG11, the gene associated with the major locus involved, encodes spatacsin, a protein of unknown function.
Methods: Different types of mutations were identified in patients with the complex form of HSP (cHSP) including TCC. We screened a series of 45 index patients with different types of cHSP with (n = 10) and without (n = 35) TCC.
Results: Ten mutations, of which five are novel, were detected in seven patients. Of importance, three out of seven mutated patients present with cHSP without TCC. Among the novel mutations identified, we characterised a large intragenic rearrangement deleting 2.6 kb of the SPG11 gene. The rearrangement is due to non-allelic homologous recombination between Alu sequences flanking the breakpoints.
Conclusions: These findings expand the mutation spectrum of SPG11 and suggest that SPG11 mutations may occur more frequently in familial than sporadic forms of cHSP without TCC. This helps to define further clinical and molecular criteria for a correct diagnosis of the SPG11 related form of cHSP. In addition, the intragenic deletion detected here, and the mechanism involved, both provide clues to address the issue of SPG11 missing mutant alleles previously reported.
Footnotes
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‣ An additional figure is published online only athttp://jmg.bmj.com/content/vol46/issue5
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Funding: The work was supported by the Italian Ministry of Health funds RF2007-75 (MTB, AM, AT) and PS-NEURO ex art.56/05/7 (MTB, NB)
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Competing interests: None.
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Patient consent: Obtained.
