title: A de novo SPAST mutation leading to somatic mosaicism is associated with a later age at onset in HSP.
abstract: SPG4/SPAST, the gene-encoding spastin, is responsible for the most frequent form of autosomal dominant hereditary spastic paraplegia (HSP). SPG4-HSP is a heterogeneous disorder characterized by both interfamilial and intrafamilial variation, especially regarding the severity and the age at onset. In this study, we investigated the origin of the mutation and the factors involved in intra-familial heterogeneity in a family with a SPG4 mutation. We demonstrated that the mutation occurred de novo and show evidence of somatic mosaicism in the grandfather, who was the only affected member of six siblings. His disease began at age 55, much later than in his daughter, who had onset at age 18, and his grandson, in whom onset was at age 5. These observations indicate that de novo mutations can occur in SPG4, and that somatic mosaicism might account for intra-familial variation in SPG4-linked HSP.
authors.forename: Christel
authors.initials: C
authors.lastname: Depienne
authors.forename: Estelle
authors.initials: E
authors.lastname: Fedirko
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Faucheux
authors.forename: Sylvie
authors.initials: S
authors.lastname: Forlani
authors.forename: Bernard
authors.initials: B
authors.lastname: Bricka
authors.forename: Cyril
authors.initials: C
authors.lastname: Goizet
authors.forename: Sylvie
authors.initials: S
authors.lastname: Lesourd
authors.forename: Giovanni
authors.initials: G
authors.lastname: Stevanin
authors.forename: Merle
authors.initials: M
authors.lastname: Ruberg
authors.forename: Alexandra
authors.initials: A
authors.lastname: Durr
authors.forename: Alexis
authors.initials: A
authors.lastname: Brice
mesh_terms: D000251:Adenosine Triphosphatases / Q000235:genetics*; D000293:Adolescent; D017668:Age of Onset; D002675:Child, Preschool; D005190:Family; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009030:Mosaicism; D010264:Paraplegia / Q000235:genetics*; D010375:Pedigree; D000074181:Spastin
chemical_list: D000251:Adenosine Triphosphatases; D000074181:Spastin; C400283:SPAST protein, human