Journal
EPILEPSIA
Volume 51, Issue 12, Pages 2397-2405Publisher
WILEY-BLACKWELL PUBLISHING, INC
DOI: 10.1111/j.1528-1167.2010.02728.x
Keywords
STXBP1; EIEE; West syndrome; Haploinsufficiency
Categories
Funding
- Ministry of Health, Labour and Welfare
- Ministry of Education, Culture, Sports, Science and Technology of Japan
- Japan Society for the Promotion of Science
- Yokohama Foundation for Advancement of Medical Science
- Uehara Memorial Foundation
- Japan Epilepsy Research Foundation
- Yokohama City University
- Naito Foundation
- Grants-in-Aid for Scientific Research [22689011, 21591312] Funding Source: KAKEN
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P>Purpose: De novo STXBP1 mutations have been found in individuals with early infantile epileptic encephalopathy with suppression-burst pattern (EIEE). Our aim was to delineate the clinical spectrum of subjects with STXBP1 mutations, and to examine their biologic aspects. Methods: STXBP1 was analyzed in 29 and 54 cases of cryptogenic EIEE and West syndrome, respectively, as a second cohort. RNA splicing was analyzed in lymphoblastoid cells from a subject harboring a c.663 + 5G > A mutation. Expression of STXBP1 protein with missense mutations was examined in neuroblastoma2A cells. Results: A total of seven novel STXBP1 mutations were found in nine EIEE cases, but not in West syndrome. The mutations include two frameshift mutations, three nonsense mutations, a splicing mutation, and a recurrent missense mutation in three unrelated cases. Including our previous data, 10 of 14 individuals (71%) with STXBP1 aberrations had the onset of spasms after 1 month, suggesting relatively later onset of epileptic spasms. Nonsense-mediated mRNA decay associated with abnormal splicing was demonstrated. Transient expression revealed that STXBP1 proteins with missense mutations resulted in degradation in neuroblastoma2A cells. Discussion: Collectively, STXBP1 aberrations can account for about one-third individuals with EIEE (14 of 43). These genetic and biologic data clearly showed that haploinsufficiency of STXBP1 is the important cause for cryptogenic EIEE.
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