Mutation analysis of the spastin gene (SPG4) in patients with hereditary spastic paraparesis.
BACKGROUND
Hereditary spastic paraparesis is a genetically heterogeneous condition. Recently, mutations in the spastin gene were reported in families linked to the common SPG4 locus on chromosome 2p21-22.


OBJECTIVE
To study a population of patients with hereditary spastic paraparesis for mutations in the spastin gene (SPG4) on chromosome 2p21-22.


METHODS
DNA from 32 patients (12 from families known to be linked to SPG4) was analysed for mutations in the spastin gene by single strand conformational polymorphism analysis and sequencing. All patients were also examined clinically.


RESULTS
Thirteen SPG4 mutations were identified, 11 of which are novel. These mutations include missense, nonsense, frameshift, and splice site mutations, the majority of which affect the AAA cassette. We also describe a nucleotide substitution outside this conserved region which appears to behave as a recessive mutation.


CONCLUSIONS
Recurrent mutations in the spastin gene are uncommon. This reduces the ease of mutation detection as a part of the diagnostic work up of patients with hereditary spastic paraparesis. Our findings have important implications for the presumed function of spastin and schemes for mutation detection in HSP patients.
Lindsey
J C
JC
Human Molecular Genetics Unit, School of Biochemistry and Genetics, University of Newcastle upon Tyne, Newcastle upon Tyne NE2 4AA, UK.
Lusher
M E
ME
McDermott
C J
CJ
White
K D
KD
Reid
E
E
Rubinsztein
D C
DC
Bashir
R
R
Hazan
J
J
Shaw
P J
PJ
Bushby
K M
KM
D000251:Adenosine Triphosphatases; D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000368:Aged; D000369:Aged, 80 and over; D001483:Base Sequence; D002135:Calcium-Binding Proteins / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D002889:Chromosomes, Human, Pair 2 / Q000235:genetics; D004252:DNA Mutational Analysis; D005260:Female; D005808:Genes, Recessive / Q000235:genetics; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D020336:Paraparesis, Spastic / Q000453:epidemiology / Q000235:genetics* / Q000503:physiopathology; D010641:Phenotype; D018807:Polymorphism, Single-Stranded Conformational; D000074181:Spastin; D006113:United Kingdom
D002135:Calcium-Binding Proteins; D000251:Adenosine Triphosphatases; D000074181:Spastin; C400283:SPAST protein, human