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Human Molecular Genetics, 2000, Vol. 9, No. 4 637-644
© 2000 Oxford University Press

Spectrum of SPG4 mutations in autosomal dominant spastic paraplegia

Nùria Fonknechten1, Delphine Mavel1, Paula Byrne2, Claire-Sophie Davoine3, Corinne Cruaud1, Dominikus Boentsch4, Delphine Samson1, Paula Coutinho5, Michael Hutchinson6, Paul Mc Monagle6, Jean-Marc Burgunder7, Antonio Tartaglione8, Olivier Heinzlef9, Imed Feki10,11, Thomas Deufel4, Nollaig Parfrey2, Alexis Brice10,11,12, Bertrand Fontaine3,11, Jean-François Prud’homme13, Jean Weissenbach1, Alexandra Dürr10,11,12 and Jamilé Hazan1,+

1Genoscope, 2 rue Gaston Crémieux, 91000 Evry, France, 2Department of Pathology, University College Dublin, Dublin, Ireland, 3INSERM CJF9711, Faculté de Médecine Pitié-Salpêtrière, Paris, France, 4Institut für Klinische Chemie und Laboratoriumsdiagnostik, Klinikum der Friedrich-Schiller-Universität Jena, Jena, Germany, 5Servicio de Neurologia, Departamento de Medicine, Santa Maria de Feira, Portugal, 6Department of Neurology, St Vincent’s University Hospital, Dublin, Ireland, 7Neurologische Klinik und Poliklinik, Universitätsspital Bern, Bern, Switzerland, 8Divisione di Neurologia, Hospidale Civile S. Andrea, La Spezia, Italy, 9Service de Neurologie, Hôpital Tenon, Paris, France, 10INSERM U289, 11Fédération de Neurologie and 12Consultation de Génétique Médicale, Groupe Hospitalier Pitié-Salpêtrière, Paris, France and 13Généthon, Evry, France

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.

+ To whom correspondence should be addressed. Tel: +33 1 60 87 25 60; Fax: +33 1 60 87 25 89; Email: jamile@genoscope.cns.fr


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