Early onset autosomal dominant spastic paraplegia caused by novel mutations in SPG3A
- 180 Downloads
Hereditary spastic paraplegia (HSP) is a group of neurodegenerative disorders mainly characterized by progressive spasticity of the lower limbs. The major features of HSP are a marked phenotypic variability both among and within families and an extended genetic heterogeneity. More than 20 HSP loci and 10 spastic paraplegia genes ( SPG) have been identified to date, including the genes responsible for the two most frequent forms of autosomal dominant spastic paraplegia (AD-HSP), encoding spastin ( SPG4) and atlastin ( SPG3A), respectively. To date, only eight mutations have been described in the atlastin gene, which was reported to account for about 10% of all AD-HSP families. We investigated 15 German and French AD-HSP families, including the 3 large pedigrees that allowed the mapping and subsequent refinement of the SPG3A locus. Three novel mutations were found in exons 4, 9, and 12 of the atlastin gene and the common R239C mutation located in exon 7 was confirmed in a 7th family of European origin. Overall, the comparison of the clinical data for all SPG3A-HSP families reported to date failed to reveal any genotype/phenotype correlation as demonstrated for other forms of AD-HSP. However, it confirmed the early onset of this form of HSP, which was observed in almost all affected individuals with a mutation in the atlastin gene.
KeywordsHereditary spastic paraplegia Novel mutations SPG3A
We are grateful to the HSP patients and their families, and to Professor Jean de Recondo and Dr. Catherine Lamy for their invaluable assistance. We thank Professor Bertrand Fontaine, Dr. Caroline Paternotte and Claire-Sophie Davoine for their participation in the initial study and the DNA and cell bank from IFR070 for DNA preparation. This work was partly supported by the DFG (Deutsche Forschungsgemeinschaft) and the Verum Foundation. Genbank accession numbers for sequences in protein alignment: Homo sapiens atlastin, guanylate-binding protein 3 (NP_056999), Homo sapiens ADP-ribosylation factor-like 6 interacting protein 2 (NM_022374), Homo sapiens cDNA FLJ40269 fls clone TEST12026597 (AK097588), Mus musculus atlastin (NP_848743), Drosophila melanogaster atlastin (CG6668), Caenorhabditis elegans atlastin (AAK68527).
- 1.Fink JK (2003) Advances in the hereditary spastic paraplegias. Exp Neurol 184 [Suppl 1]:S106–S110Google Scholar
- 4.Hazan J, Fonknechten N, Mavel D, Paternotte C, Samson D, Artiguenave F, Davoine CS, Cruaud C, Durr A, Wincker P, Brottier P, Cattolico L, Barbe V, Burgunder JM, Prud’homme JF, Brice A, Fontaine B, Heilig B, Weissenbach J (1999) Spastin, a new AAA protein, is altered in the most frequent form of autosomal dominant spastic paraplegia. Nat Genet 23:296–303CrossRefPubMedGoogle Scholar
- 13.Paternotte C, Rudnicki D, Fizames C, Davoine CS, Mavel D, Durr A, Samson D, Marquette C, Muselet D, Vega-Czarny N, Drouot N, Voit T, Fontaine B, Gyapay G, Auburger G, Weissenbach J, Hazan J (1998) Quality assessment of whole genome mapping data in the refined familial spastic paraplegia interval on chromosome 14q. Genome Res 8:1216–1227PubMedGoogle Scholar
- 14.Muglia M, Magariello A, Nicoletti G, Patitucci A, Gabriele AL, Conforti FL, Mazzei R, Caracciolo M, Casari G, Ardito B, Lastilla M, Gambardella A, Quattrone A (2002) A large family with pure autosomal dominant hereditary spastic paraplegia from southern Italy mapping to chromosome 14q11.2-q24.3. J Neurol 249:1413–1416CrossRefPubMedGoogle Scholar
- 16.Dürr A, Camuzat A, Colin E, Tallaksen C, Hannequin D, Coutinho P, Fontaine B, Rossi A, Gil R, Rousselle C, Ruberg M, Stevanin G, Brice A (2004) Atlastin1 mutations are frequent in young onset autosomal dominant spastic paraplegia. Arch Neurol (in press)Google Scholar
- 17.Fonknechten N, Mavel D, Byrne P, Davoine CS, Cruaud C, Boentsch D, Samson D, Coutinho P, Hutchinson M, McMonagle P, Burgunder JM, Tartaglione A, Heinzlef O, Feki I, Deufel T, Parfrey N, Brice A, Fontaine B, Prud’homme JF, Weissenbach J, Dürr A, Hazan J (2000) Spectrum of SPG4 mutations in autosomal dominant spastic paraplegia. Hum Mol Genet 9:637–644CrossRefPubMedGoogle Scholar