Role of SOX2 mutations in human hippocampal malformations and epilepsy.
OBJECTIVE
Seizures are noted in a significant proportion of cases of de novo, heterozygous, loss-of-function mutations in SOX2, ascertained because of severe bilateral eye malformations. We wished to determine the underlying cerebral phenotype in SOX2 mutation and to test the candidacy of SOX2 as a gene contributing to human epilepsies.


METHODS
We examined high-resolution MRI scans in four patients with SOX2 mutations, two of whom had seizures. We determined the Sox2 expression pattern in developing murine brain. We searched for SOX2 mutation in 24 patients with typical hippocampal sclerosis and for common variations in SOX2 in 655 patients without eye disease but with epilepsy, including 91 patients with febrile seizures, 93 with hippocampal sclerosis, and 258 with temporal lobe epilepsy.


RESULTS
Striking hippocampal and parahippocampal malformations were seen in all cases, with a history of febrile seizures or epilepsy in two of four cases. The Sox2 expression pattern in developing mouse brain supports the pattern of malformations observed. Mutation screening in patients with epilepsy did not reveal any abnormalities in SOX2. No associations were found between any clinical epilepsy phenotype and common variation in SOX2.


CONCLUSIONS
SOX2 haploinsufficiency causes mesial temporal malformation in humans, making SOX2 dysfunction a candidate mechanism for mesial temporal abnormalities associated with chronic epilepsy. However, although mutation of SOX2 in humans causes hippocampal malformation, SOX2 mutation or variation is unlikely to contribute commonly to mesial temporal lobe epilepsy or its structural (hippocampal sclerosis) or historic (febrile seizures) associations in humans.
Sisodiya
Sanjay M
SM
Department of Clinical and Experimental Epilepsy, Institute of Neurology, UCL, London, and National Society for Epilepsy, Bucks SL90RJ, London, UK. sisodiya@ion.ucl.ac.uk
Ragge
Nicola K
NK
Cavalleri
Gianpiero L
GL
Hever
Ann
A
Lorenz
Birgit
B
Schneider
Adele
A
Williamson
Kathleen A
KA
Stevens
John M
JM
Free
Samantha L
SL
Thompson
Pamela J
PJ
van Heyningen
Veronica
V
Fitzpatrick
David R
DR
D000293:Adolescent; D000818:Animals; D002648:Child; D004827:Epilepsy / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D004833:Epilepsy, Temporal Lobe / Q000235:genetics; D005124:Eye Abnormalities / Q000235:genetics; D005136:Eye Proteins / Q000235:genetics; D005260:Female; D007839:Functional Laterality; D015870:Gene Expression; D014644:Genetic Variation; D024002:HMGB Proteins / Q000235:genetics*; D006239:Haplotypes; D006624:Hippocampus / Q000002:abnormalities* / Q000473:pathology; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D008279:Magnetic Resonance Imaging; D008297:Male; D051379:Mice; D009154:Mutation / Q000235:genetics*; D000071841:PAX6 Transcription Factor; D051761:Paired Box Transcription Factors / Q000235:genetics; D010641:Phenotype; D012097:Repressor Proteins / Q000235:genetics; D055748:SOXB1 Transcription Factors; D012598:Sclerosis / Q000235:genetics / Q000473:pathology; D003294:Seizures, Febrile / Q000235:genetics; D013702:Temporal Lobe / Q000473:pathology; D014157:Transcription Factors / Q000235:genetics*
D005136:Eye Proteins; D024002:HMGB Proteins; D018398:Homeodomain Proteins; D000071841:PAX6 Transcription Factor; C000605730:PAX6 protein, human; D051761:Paired Box Transcription Factors; C000605732:Pax6 protein, mouse; D012097:Repressor Proteins; C527782:SOX2 protein, human; D055748:SOXB1 Transcription Factors; C527783:Sox2 protein, mouse; D014157:Transcription Factors