title: Dominant-negative mutations in alpha-II spectrin cause West syndrome with severe cerebral hypomyelination, spastic quadriplegia, and developmental delay.
abstract: A de novo 9q33.3-q34.11 microdeletion involving STXBP1 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 STXBP1 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 zebrafish, turned out to be deleted. In two subjects, an in-frame 3 bp deletion and a 6 bp duplication in SPTAN1 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.affiliation: Department of Human Genetics, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan. hsaitsu@yokohama-cu.ac.jp
authors.forename: Hirotomo
authors.initials: H
authors.lastname: Saitsu
authors.forename: Jun
authors.initials: J
authors.lastname: Tohyama
authors.forename: Tatsuro
authors.initials: T
authors.lastname: Kumada
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Egawa
authors.forename: Keisuke
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authors.lastname: Hamada
authors.forename: Ippei
authors.initials: I
authors.lastname: Okada
authors.forename: Takeshi
authors.initials: T
authors.lastname: Mizuguchi
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Osaka
authors.forename: Rie
authors.initials: R
authors.lastname: Miyata
authors.forename: Tomonori
authors.initials: T
authors.lastname: Furukawa
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Haginoya
authors.forename: Hideki
authors.initials: H
authors.lastname: Hoshino
authors.forename: Tomohide
authors.initials: T
authors.lastname: Goto
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Hachiya
authors.forename: Takanori
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authors.lastname: Yamagata
authors.forename: Shinji
authors.initials: S
authors.lastname: Saitoh
authors.forename: Toshiro
authors.initials: T
authors.lastname: Nagai
authors.forename: Kiyomi
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authors.lastname: Nishiyama
authors.forename: Akira
authors.initials: A
authors.lastname: Nishimura
authors.forename: Noriko
authors.initials: N
authors.lastname: Miyake
authors.forename: Masayuki
authors.initials: M
authors.lastname: Komada
authors.forename: Kenji
authors.initials: K
authors.lastname: Hayashi
authors.forename: Syu-Ichi
authors.initials: S
authors.lastname: Hirai
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Ogata
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Kato
authors.forename: Atsuo
authors.initials: A
authors.lastname: Fukuda
authors.forename: Naomichi
authors.initials: N
authors.lastname: Matsumoto
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001921:Brain / Q000378:metabolism; D002478:Cells, Cultured; D002658:Developmental Disabilities / Q000235:genetics*; D006801:Humans; D007223:Infant; D051379:Mice; D008969:Molecular Sequence Data; D009186:Myelin Sheath / Q000378:metabolism; D010641:Phenotype; D011782:Quadriplegia / Q000235:genetics; D013036:Spasms, Infantile / Q000235:genetics; D013049:Spectrin / Q000235:genetics; D014162:Transfection
chemical_list: C452439:SPTBN1 protein, human; D013049:Spectrin