Role of SOX2 mutations in human hippocampal malformations and epilepsy

被引:72
作者
Sisodiya, SM
Ragge, NK
Cavalleri, GL
Hever, A
Lorenz, B
Schneider, A
Williamson, KA
Stevens, JM
Free, SL
Thompson, PJ
van Heyningen, V
FitzPatrick, DR
机构
[1] UCL, Dept Clin & Expt Epilepsy, Inst Neurol, London WC1N 3BG, England
[2] Moorfields Eye Hosp, Adnexal Serv, London, England
[3] Univ Oxford, Dept Human Anat & Genet, Oxford, England
[4] UCL, Dept Biol, London, England
[5] MRC, Human Genet Unit, Edinburgh, Midlothian, Scotland
[6] Univ Regensburg, Klinikum, Dept Paediat Ophthalmol & Ophthalmogenet, D-8400 Regensburg, Germany
[7] Albert Einstein Med Ctr, Dept Clin Genet, Philadelphia, PA 19141 USA
基金
英国医学研究理事会;
关键词
brain malformation; epilepsy; SOX2; hippocampal sclerosis;
D O I
10.1111/j.1528-1167.2006.00464.x
中图分类号
R74 [神经病学与精神病学];
学科分类号
摘要
Purpose: 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.
引用
收藏
页码:534 / 542
页数:9
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