SRPX2 mutations in disorders of language cortex and cognition

Hum Mol Genet. 2006 Apr 1;15(7):1195-207. doi: 10.1093/hmg/ddl035. Epub 2006 Feb 23.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Amino Acid Sequence
  • Animals
  • Apraxias / genetics
  • Apraxias / metabolism
  • Base Sequence
  • CHO Cells
  • Cerebral Cortex / metabolism*
  • Child
  • Child, Preschool
  • Cognition*
  • Cricetinae
  • Epilepsy, Rolandic / genetics
  • Epilepsy, Rolandic / metabolism
  • Female
  • Fibroblasts / metabolism
  • Genetic Linkage
  • Genetic Testing
  • Glycosylation
  • Humans
  • Immunohistochemistry
  • Intellectual Disability / metabolism
  • Language Disorders / genetics*
  • Language Disorders / metabolism
  • Language Disorders / physiopathology
  • Male
  • Membrane Proteins / genetics*
  • Membrane Proteins / metabolism
  • Mice
  • Molecular Sequence Data
  • Mutation*
  • Nerve Tissue Proteins / genetics*
  • Nerve Tissue Proteins / metabolism
  • Transfection


  • Membrane Proteins
  • Nerve Tissue Proteins
  • SRPX protein, human
  • SRPX2 protein, human