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Unexpected pathogenic mechanism of a novel mutation in the coding sequence of SPG4 (spastin)

From the Institut für Klinische Chemie und Laboratoriumsdiagnostik (J.S., C.B., C.F., A.S., and T.D.) and the Klinik für Neurologie (G.H.), Universitätsklinikum, Friedrich-Schiller Universität, and the Institut für Molekulare Biotechnologie (A.S., P.H.), Jena, Germany.

Address correspondence and reprint requests to Professor Thomas Deufel, Universitätsklinikum Jena, Institut für Klinische Chemie und Laboratoriumsdiagnostik, Erlanger Allee 101, D-07740 Jena, Germany; e-mail: thomas.deufel{at}med.uni-jena.de

The authors report a nucleotide substitution (c.1216A>G) in SPG4 (spastin) causing hereditary spastic paraplegia. This apparent missense mutation in the ATPase domain confers aberrant, in-frame splicing and results in destabilization of mutated transcript. Mutated protein is deficient in microtubule-severing activity but, unlike neighboring mutations, shows regular subcellular localization. The authors’ data point to haploinsufficiency rather than a dominant negative effect as the disease-causing mechanism for this mutation.

Supported by grants from the European Union (FP6-2002-LIFESCIHEALTH, Spastic Models to T.D.), the Interdisziplinäres Zentrum für Klinische Forschung at the Friedrich-Schiller-Universität Jena (TP1.10, to J.S.), and the Tom-Wahlig-Stiftung.

Disclosure: The authors report no conflicts of interest.

Received July 24, 2005. Accepted in final form October 27, 2005.

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