Dominant-negative mutations in alpha-II spectrin cause West syndrome with severe cerebral hypomyelination, spastic quadriplegia, and developmental delay.
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.
Saitsu
Hirotomo
H
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
Tohyama
Jun
J
Kumada
Tatsuro
T
Egawa
Kiyoshi
K
Hamada
Keisuke
K
Okada
Ippei
I
Mizuguchi
Takeshi
T
Osaka
Hitoshi
H
Miyata
Rie
R
Furukawa
Tomonori
T
Haginoya
Kazuhiro
K
Hoshino
Hideki
H
Goto
Tomohide
T
Hachiya
Yasuo
Y
Yamagata
Takanori
T
Saitoh
Shinji
S
Nagai
Toshiro
T
Nishiyama
Kiyomi
K
Nishimura
Akira
A
Miyake
Noriko
N
Komada
Masayuki
M
Hayashi
Kenji
K
Hirai
Syu-Ichi
S
Ogata
Kazuhiro
K
Kato
Mitsuhiro
M
Fukuda
Atsuo
A
Matsumoto
Naomichi
N
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
C452439:SPTBN1 protein, human; D013049:Spectrin