Missense and splice site mutations in SPG4 suggest loss-of-function in dominant spastic paraplegia.
We studied nine Italian families with a pure form of autosomal dominant spastic paraplegia (ADHSP) to assess the frequency of mutations in the SPG4 gene. We observed marked intrafamilial variability in both age-at-onset and clinical severity, ranging from severe congenital presentation to mild involvement after age 55 years to healthy carriers of the mutation after age 70. Four of nine probands harboured SPG4 mutations, We identified three new SPG4 mutations, all predicting a loss-of-func-tion with apparently important consequences for spastin function. RT-PCR studies predict loss-of-function as a possible mechanism leading to spastin-related HSP. The current study expands the spectrum of allelic variants in SPG4, confirming their pathological significance in pure AD-HSP and suggesting implications for the presumed function of spastin.
Patrono
Clarice
C
IRCCS-Children's Hospital Bambino Gesù, Rome, Italy.
Casali
Carlo
C
Tessa
Alessandra
A
Cricchi
Federica
F
Fortini
Daniela
D
Carrozzo
Rosalba
R
Siciliano
Gabriele
G
Bertini
Enrico
E
Santorelli
Filippo M
FM
D000251:Adenosine Triphosphatases / Q000235:genetics* / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000368:Aged; D017398:Alternative Splicing / Q000235:genetics*; D000595:Amino Acid Sequence / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D002889:Chromosomes, Human, Pair 2; D004252:DNA Mutational Analysis; D005091:Exons / Q000235:genetics; D005260:Female; D005787:Gene Frequency / Q000235:genetics; D005820:Genetic Testing; D006801:Humans; D007223:Infant; D007558:Italy; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense / Q000235:genetics*; D010375:Pedigree; D012333:RNA, Messenger / Q000235:genetics*; D015419:Spastic Paraplegia, Hereditary / Q000235:genetics* / Q000503:physiopathology; D000074181:Spastin
D012333:RNA, Messenger; D000251:Adenosine Triphosphatases; D000074181:Spastin; C400283:SPAST protein, human