Journal
AMERICAN JOURNAL OF HUMAN GENETICS
Volume 86, Issue 6, Pages 881-891Publisher
CELL PRESS
DOI: 10.1016/j.ajhg.2010.04.013
Keywords
-
Categories
Funding
- Ministry of Health, Labour, and Welfare
- Japan Science and Technology Agency
- 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 [21591306, 22689011] Funding Source: KAKEN
Ask authors/readers for more resources
A de novo 9q33.3-q34.11 microdeletion involving STX8P1 has been found in one of four individuals (group A) with early-onset West syndrome, severe hypomyelination, poor visual attention, and developmental delay. Although haploinsufficiency of STXBP1 was involved in early infantile epileptic encephalopathy in a previous different cohort study (group B), no mutations of SIXBP1 were found in two of the remaining three subjects of group A (one was unavailable), We assumed that another gene within the deletion might contribute to the phenotype of group A. SPTAN1 encoding alpha-II spectrin, which is essential for proper myelination in zebratish, turned out to be deleted. In two subjects, an in-frame 3 bp deletion and a 6 bp duplication in SHAN1 were found at the initial nucleation site of the alpha/beta spectrin heterodimer. SPTAN1 was further screened in six unrelated individuals with WS and hypomyelination, but no mutations were found. Recombinant mutant (mut) and wild-type (WT) alpha-II spectrin could assemble heterodimers with beta-II spectrin, but alpha-II (mut)/beta-II spectrin heterodimers were thermolabile compared with the alpha-II (WT)/beta-II heterodimers. Transient expression in mouse cortical neurons revealed aggregation of alpha-II (mut)/beta-II and alpha-II (mut)/beta-III spectrin heterodimers, which was also observed in lymphoblastoid cells from two subjects with in-frame mutations. Clustering of ankyrinG and voltage-gated sodium channels at axon initial segment (AIS) was disturbed in relation to the aggregates, together with an elevated action potential threshold. These findings suggest that pathological aggregation of alpha/beta spectrin heterodimers and abnormal AIS integrity resulting from SPTAN1 mutations were involved in pathogenesis of infantile epilepsy.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available