SRPX2 mutations in disorders of language cortex and cognition.
The rolandic and sylvian fissures divide the human cerebral hemispheres and the adjacent areas participate in speech processing. The relationship of rolandic (sylvian) seizure disorders with speech and cognitive impairments is well known, albeit poorly understood. We have identified the Xq22 gene SRPX2 as being responsible for rolandic seizures (RSs) associated with oral and speech dyspraxia and mental retardation (MR). SRPX2 is a secreted sushi-repeat containing protein expressed in neurons of the human adult brain, including the rolandic area. The disease-causing mutation (N327S) resulted in gain-of-glycosylation of the secreted mutant protein. A second mutation (Y72S) was identified within the first sushi domain of SRPX2 in a male with RSs and bilateral perisylvian polymicrogyria and his female relatives with mild MR or unaffected carrier status. In cultured cells, both mutations were associated with altered patterns of intracellular processing, suggesting protein misfolding. In the murine brain, Srpx2 protein expression appeared in neurons at birth. The involvement of SRPX2 in these disorders suggests an important role for SRPX2 in the perisylvian region critical for language and cognitive development.
INSERM UMR491, Université de la Méditerranée, 13385 Marseille, France.
Patrice
P
Roll
Gabrielle
G
Rudolf
Sandrine
S
Pereira
Barbara
B
Royer
Ingrid E
IE
Scheffer
Annick
A
Massacrier
Maria-Paola
MP
Valenti
Nathalie
N
Roeckel-Trevisiol
Sarah
S
Jamali
Christophe
C
Beclin
Caroline
C
Seegmuller
Marie-Noëlle
MN
Metz-Lutz
Arnaud
A
Lemainque
Marc
M
Delepine
Christophe
C
Caloustian
Anne
A
de Saint Martin
Nadine
N
Bruneau
Danièle
D
Depétris
Marie-Geneviève
MG
Mattéi
Elisabeth
E
Flori
Andrée
A
Robaglia-Schlupp
Nicolas
N
Lévy
Bernd A
BA
Neubauer
Rivka
R
Ravid
Christian
C
Marescaux
Samuel F
SF
Berkovic
Edouard
E
Hirsch
Mark
M
Lathrop
Pierre
P
Cau
Pierre
P
Szepetowski
D000328:Adult; D000595:Amino Acid Sequence; D000818:Animals; D001072:Apraxias / Q000235:genetics / Q000378:metabolism; D001483:Base Sequence; D016466:CHO Cells; D002540:Cerebral Cortex / Q000378:metabolism*; D002648:Child; D002675:Child, Preschool; D003071:Cognition; D006224:Cricetinae; D019305:Epilepsy, Rolandic / Q000235:genetics / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D008040:Genetic Linkage; D005820:Genetic Testing; D006031:Glycosylation; D006801:Humans; D007150:Immunohistochemistry; D008607:Intellectual Disability / Q000378:metabolism; D007806:Language Disorders / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D014162:Transfection
D008565:Membrane Proteins; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; C486297:SRPX protein, human; C116881:SRPX2 protein, human