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Human Molecular Genetics Advance Access originally published online on February 23, 2006
Human Molecular Genetics 2006 15(7):1195-1207; doi:10.1093/hmg/ddl035
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© The Author 2006. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

SRPX2 mutations in disorders of language cortex and cognition

Patrice Roll1,10, Gabrielle Rudolf3, Sandrine Pereira1, Barbara Royer1, Ingrid E. Scheffer6, Annick Massacrier1, Maria-Paola Valenti3, Nathalie Roeckel-Trevisiol1, Sarah Jamali1, Christophe Beclin7, Caroline Seegmuller3, Marie-Noëlle Metz-Lutz3,8, Arnaud Lemainque9, Marc Delepine9, Christophe Caloustian9, Anne de Saint Martin4, Nadine Bruneau2, Danièle Depétris1, Marie-Geneviève Mattéi1, Elisabeth Flori5, Andrée Robaglia-Schlupp1,10, Nicolas Lévy1,11, Bernd A. Neubauer12, Rivka Ravid13, Christian Marescaux3, Samuel F. Berkovic6, Edouard Hirsch3, Mark Lathrop9, Pierre Cau1,10 and Pierre Szepetowski1,*

1INSERM UMR491 and 2INSERM U559, Université de la Méditerranée, 13385 Marseille, France, 3Clinique Neurologique, 4Département de Neuropédiatrie and 5Laboratoire de Cytogénétique, Hôpitaux Universitaires, 67091 Strasbourg, France, 6Department of Medicine, The University of Melbourne, 3081 Australia, 7IMVT, IBDM, 13288 Marseille, France, 8CNRS UMR7004, 67085 Strasbourg, France, 9Centre National de Génotypage (CNG), 91057 Evry, France, 10Laboratoire de Biologie Cellulaire, AP-HM, 13385 Marseille, France, 11Département de Génétique Médicale, AP-HM, 13385 Marseille, France and 12Department of Neuropediatrics, University of Giessen, Giessen D-35385, Germany and 13Netherlands Brain Bank, Amsterdam 1105 AZ, The Netherlands

* To whom correspondence should be addressed at: INSERM UMR491, ‘Genetics of Human Epilepsies’ Group, Faculté de Médecine de la Timone, 27 Bd J Moulin, 13385 Marseille Cedex 5, France. Tel: +33 491324386; Fax: +33 491804319; Email: szepetowski{at}medecine.univ-mrs.fr

Received November 11, 2005; Revised January 16, 2006; Accepted February 15, 2006

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.


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