Spectrum of SPG4 mutations in autosomal dominant spastic paraplegia

Authors: Fonknechten, Nùria¹; Mavel, Delphine¹; Byrne, Paula²; Davoine, Claire-Sophie³; Cruaud, Corinne¹; Boentsch, Dominikus⁴; Samson, Delphine¹; Coutinho, Paula⁵; Hutchinson, Michael⁶; Monagle, Paul Mc⁶; Burgunder, Jean-Marc⁷; Tartaglione, Antonio⁸; Heinzlef, Olivier⁹; Feki, Imed¹⁰; Deufel, Thomas⁴; Parfrey, Nollaig²; Brice, Alexis¹⁰; Fontaine, Bertrand³; Prud’homme, Jean-François¹¹; Weissenbach, Jean¹; Dürr, Alexandra¹⁰; Hazan, Jamilé¹

Source: Human Molecular Genetics, Volume 9, Number 4, 1 March 2000 , pp. 637-644(8)

Publisher: Oxford University Press

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Abstract:

Autosomal dominant hereditary spastic paraplegia (AD-HSP) is a group of genetically heterogeneous neurodegenerative disorders characterized by pro- gressive spasticity of the lower limbs. Five AD-HSP loci have been mapped to chromosomes 14q, 2p, 15q, 8q and 12q. The SPG4 locus at 2p21–p22 has been shown to account for 40% of all AD-HSP families. SPG4 encoding spastin, a putative nuclear AAA protein, has recently been identified. Here, sequence analysis of the 17 exons of SPG4 in 87 unrelated AD-HSP patients has resulted in the detection of 34 novel mutations. These SPG4 mutations are scattered along the coding region of the gene and include all types of DNA modification including missense (28%), nonsense (15%) and splice site point (26.5%) mutations as well as deletions (23%) and insertions (7.5%). The clinical analysis of the 238 mutation carriers revealed a high proportion of both asymptomatic carriers (14/238) and patients unaware of symptoms (45/238), and permitted the redefinition of this frequent form of AD-HSP.

Document Type: Research article

Affiliations: 1: Genoscope, 2 rue Gaston Crémieux, 91000 Evry, France, 10: INSERM U289, 11: Généthon, Evry, France 2: Department of Pathology, University College Dublin, Dublin, Ireland, 3: INSERM CJF9711, Faculté de Médecine Pitié-Salpêtrière, Paris, France, 4: Institut für Klinische Chemie und Laboratoriumsdiagnostik, Klinikum der Friedrich-Schiller-Universität Jena, Jena, Germany, 5: Servicio de Neurologia, Departamento de Medicine, Santa Maria de Feira, Portugal, 6: Department of Neurology, St Vincent’s University Hospital, Dublin, Ireland, 7: Neurologische Klinik und Poliklinik, Universitätsspital Bern, Bern, Switzerland, 8: Divisione di Neurologia, Hospidale Civile S. Andrea, La Spezia, Italy, 9: Service de Neurologie, Hôpital Tenon, Paris, France,

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