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Human Molecular Genetics Advance Access published online on February 23, 2006
Human Molecular Genetics, doi:10.1093/hmg/ddl035
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© The Author 2006. Published by Oxford University Press. All rights reserved
Received November 11, 2005
Revised January 16, 2006
Accepted February 15, 2006

Article

SRPX2 mutations in disorders of language cortex and cognition

Patrice Roll 1, Gabrielle Rudolf 2, Sandrine Pereira 1, Barbara Royer 1, Ingrid E. Scheffer 3, Annick Massacrier 1, Maria-Paola Valenti 2, Nathalie Roeckel-Trevisiol 1, Sarah Jamali 1, Christophe Beclin 4, Caroline Seegmuller 2, Marie-Noëlle Metz-Lutz 5, Arnaud Lemainque 6, Marc Delepine 6, Christophe Caloustian 6, Anne de Saint Martin 7, Nadine Bruneau 8, Danièle Depétris 1, Marie-Geneviève Mattéi 1, Elisabeth Flori 9, Andrée Robaglia-Schlupp 10, Nicolas Lévy 11, Bernd A. Neubauer 12, Rivka Ravid 13, Christopher A. Walsh 14, Christian Marescaux 2, Samuel F. Berkovic 3, Edouard Hirsch 2, Mark Lathrop 6, Pierre Cau 10, and Pierre Szepetowski 15 *

1 INSERM UMR491, Université de la Méditerranée, 13385 Marseille, France
2 Clinique Neurologique, Hôpitaux Universitaires, 67091 Strasbourg, France
3 Department of Medicine, the University of Melbourne, 3081 Australia
4 CNRS UMR7004, 67085 Strasbourg, France
5 Clinique Neurologique, Hôpitaux Universitaires, 67091 Strasbourg, France; IMVT, IBDM, 13288 Marseille, France
6 Centre National de Génotypage (CNG), 91057 Evry, France
7 Département de Neuropédiatrie, Hôpitaux Universitaires, 67091 Strasbourg, France
8 INSERM U559, Université de la Méditerranée, 13385 Marseille, France
9 Laboratoire de Cytogénétique, Hôpitaux Universitaires, 67091 Strasbourg, France
10 INSERM UMR491, Université de la Méditerranée, 13385 Marseille, France; Laboratoire de Biologie Cellulaire, AP-HM, 13385 Marseille, France
11 INSERM UMR491, Université de la Méditerranée, 13385 Marseille, France; Département de Génétique Médicale, AP-HM, 13385 Marseille, France
12 Department of Neuropediatrics, University of Giessen, D-35385, Germany
13 Netherlands Brain Bank, Amsterdam, 1105 AZ, The Netherlands
14 Harvard Medical School, Boston, MA 02115, USA
15 INSERM UMR491, ‘Genetics of Human Epilepsies’ Group, Faculté de Médecine de la Timone, Université de la Méditerranée, 27 Bd J Moulin, 13385 Marseille, Cedex 5, France

* To whom correspondence should be addressed.
Pierre Szepetowski, E-mail: szepetowski{at}medecine.univ-mrs.fr


  Abstract

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 associated with oral and speech dyspraxia and mental retardation. 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 rolandic seizures and bilateral perisylvian polymicrogyria and his female relatives with mild mental retardation 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.


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