title: Hereditary spastic paraplegia caused by mutations in the SPG4 gene.
abstract: Autosomal dominant hereditary spastic paraplegia (AD-HSP) is a genetically heterogeneous neurodegenerative disorder characterised by progressive spasticity of the lower limbs. The SPG4 locus at 2p21-p22 accounts for 40-50% of all AD-HSP families. The SPG4 gene was recently identified. It is ubiquitously expressed in adult and foetal tissues and encodes spastin, an ATPase of the AAA family. We have now identified four novel SPG4 mutations in German AD-HSP families, including one large family for which anticipation had been proposed. Mutations include one frame-shift and one missense mutation, both affecting the Walker motif B. Two further mutations affect two donor splice sites in introns 12 and 16, respectively. RT-PCR analysis of both donor splice site mutations revealed exon skipping and reduced stability of aberrantly spliced SPG4 mRNA. All mutations are predicted to cause loss of functional protein. In conclusion, we confirm in German families that SPG4 mutations cause AD-HSP. Our data suggest that SPG4 mutations exert their dominant effect not by gain of function but by haploinsufficiency. If a threshold level of spastin were critical for axonal preservation, such threshold dosage effects might explain the variable expressivity and incomplete penetrance of SPG4-linked AD-HSP.
authors.affiliation: Institute of Human Genetics, Charité, Humboldt-Universität, Berlin, Germany. joachim.buerger@charite.de
authors.forename: J
authors.initials: J
authors.lastname: Bürger
authors.forename: N
authors.initials: N
authors.lastname: Fonknechten
authors.forename: M
authors.initials: M
authors.lastname: Hoeltzenbein
authors.forename: L
authors.initials: L
authors.lastname: Neumann
authors.forename: E
authors.initials: E
authors.lastname: Bratanoff
authors.forename: J
authors.initials: J
authors.lastname: Hazan
authors.forename: A
authors.initials: A
authors.lastname: Reis
mesh_terms: D000251:Adenosine Triphosphatases / Q000235:genetics* / Q000378:metabolism; D018389:Codon, Nonsense / Q000235:genetics*; D017931:DNA Primers / Q000737:chemistry; D005091:Exons / Q000235:genetics*; D005260:Female; D016368:Frameshift Mutation / Q000235:genetics*; D005799:Genes, Dominant; D005838:Genotype; D006801:Humans; D008297:Male; D020125:Mutation, Missense; D010375:Pedigree; D010641:Phenotype; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D012326:RNA Splicing / Q000235:genetics; D015183:Restriction Mapping; D017422:Sequence Analysis, DNA; D015419:Spastic Paraplegia, Hereditary / Q000235:genetics*; D000074181:Spastin; D018911:Trinucleotide Repeats / Q000235:genetics*
chemical_list: D018389:Codon, Nonsense; D017931:DNA Primers; D000251:Adenosine Triphosphatases; D000074181:Spastin; C400283:SPAST protein, human