title: Missense and splice site mutations in SPG4 suggest loss-of-function in dominant spastic paraplegia.
abstract: 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.
authors: IRCCS-Children's Hospital Bambino Gesù, Rome, Italy.
authors: Clarice
authors: C
authors: Patrono
authors: Carlo
authors: C
authors: Casali
authors: Alessandra
authors: A
authors: Tessa
authors: Federica
authors: F
authors: Cricchi
authors: Daniela
authors: D
authors: Fortini
authors: Rosalba
authors: R
authors: Carrozzo
authors: Gabriele
authors: G
authors: Siciliano
authors: Enrico
authors: E
authors: Bertini
authors: Filippo M
authors: FM
authors: Santorelli
mesh_terms: 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
chemical_list: D012333:RNA, Messenger; D000251:Adenosine Triphosphatases; D000074181:Spastin; C400283:SPAST protein, human