Mutations in SPG11, encoding spatacsin, are a major cause of spastic paraplegia with thin corpus callosum.
Autosomal recessive hereditary spastic paraplegia (ARHSP) with thin corpus callosum (TCC) is a common and clinically distinct form of familial spastic paraplegia that is linked to the SPG11 locus on chromosome 15 in most affected families. We analyzed 12 ARHSP-TCC families, refined the SPG11 candidate interval and identified ten mutations in a previously unidentified gene expressed ubiquitously in the nervous system but most prominently in the cerebellum, cerebral cortex, hippocampus and pineal gland. The mutations were either nonsense or insertions and deletions leading to a frameshift, suggesting a loss-of-function mechanism. The identification of the function of the gene will provide insight into the mechanisms leading to the degeneration of the corticospinal tract and other brain structures in this frequent form of ARHSP.
Stevanin
Giovanni
G
INSERM, UMR679, Federal Institute for Neuroscience Research, Pitié-Salpêtrière Hospital, Paris, France. stevanin@ccr.jussieu.fr
Santorelli
Filippo M
FM
Azzedine
Hamid
H
Coutinho
Paula
P
Chomilier
Jacques
J
Denora
Paola S
PS
Martin
Elodie
E
Ouvrard-Hernandez
Anne-Marie
AM
Tessa
Alessandra
A
Bouslam
Naïma
N
Lossos
Alexander
A
Charles
Perrine
P
Loureiro
José L
JL
Elleuch
Nizar
N
Confavreux
Christian
C
Cruz
Vítor T
VT
Ruberg
Merle
M
Leguern
Eric
E
Grid
Djamel
D
Tazir
Meriem
M
Fontaine
Bertrand
B
Filla
Alessandro
A
Bertini
Enrico
E
Durr
Alexandra
A
Brice
Alexis
A
D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000818:Animals; D001483:Base Sequence; D019556:COS Cells; D002540:Cerebral Cortex / Q000378:metabolism; D002648:Child; D002522:Chlorocebus aethiops; D002884:Chromosomes, Human, Pair 15; D003337:Corpus Callosum / Q000473:pathology*; D004252:DNA Mutational Analysis; D008040:Genetic Linkage; D005838:Genotype; D006801:Humans; D008126:Lod Score; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D011506:Proteins / Q000235:genetics* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015419:Spastic Paraplegia, Hereditary / Q000235:genetics* / Q000473:pathology*
D011506:Proteins; C520412:SPG11 protein, human