Missense and splice site mutations in SPG4 suggest loss-of-function in dominant spastic paraplegia.

Publisher: Springer-Verlag Country of Publication: Germany NLM ID: 0423161 Publication Model: Print Cited Medium: Print ISSN: 0340-5354 (Print) Linking ISSN: 03405354 NLM ISO Abbreviation: J Neurol Subsets: MEDLINE

Original Publication: Berlin ; New York, Springer-Verlag

Adenosine Triphosphatases/*genetics ; Alternative Splicing/*genetics ; Mutation, Missense/*genetics ; RNA, Messenger/*genetics ; Spastic Paraplegia, Hereditary/*genetics; Adenosine Triphosphatases/metabolism ; Adolescent ; Adult ; Age of Onset ; Aged ; Amino Acid Sequence/genetics ; Child ; Child, Preschool ; Chromosomes, Human, Pair 2 ; DNA Mutational Analysis ; Exons/genetics ; Female ; Gene Frequency/genetics ; Genetic Testing ; Humans ; Infant ; Italy ; Male ; Middle Aged ; Pedigree ; Spastic Paraplegia, Hereditary/physiopathology ; Spastin

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.

0 (RNA, Messenger)
EC 3.6.1.- (Adenosine Triphosphatases)
EC 3.6.4.3 (Spastin)
EC 5.6.1.1 (SPAST protein, human)

Date Created: 20020503 Date Completed: 20021016 Latest Revision: 20190901

20221213

10.1007/pl00007865

11985387