Dominant-Negative Mutations in α-II Spectrin Cause West Syndrome with Severe Cerebral Hypomyelination, Spastic Quadriplegia, and Developmental Delay

• Published in: American journal of human genetics Vol. 86; no. 6; pp. 881 - 891
• Main Authors: Saitsu, Hirotomo, Tohyama, Jun, Kumada, Tatsuro, Egawa, Kiyoshi, Hamada, Keisuke, Okada, Ippei, Mizuguchi, Takeshi, Osaka, Hitoshi, Miyata, Rie, Furukawa, Tomonori, Haginoya, Kazuhiro, Hoshino, Hideki, Goto, Tomohide, Hachiya, Yasuo, Yamagata, Takanori, Saitoh, Shinji, Nagai, Toshiro, Nishiyama, Kiyomi, Nishimura, Akira, Miyake, Noriko, Komada, Masayuki, Hayashi, Kenji, Hirai, Syu-ichi, Ogata, Kazuhiro, Kato, Mitsuhiro, Fukuda, Atsuo, Matsumoto, Naomichi
• Format: Journal Article
• Language: English
• Published: Cambridge, MA Elsevier Inc 11.06.2010; Cell Press; Elsevier
• Subjects: Amino Acid Sequence; Animals; Biological and medical sciences; Brain - metabolism; Cells, Cultured; Developmental Disabilities - genetics; Fundamental and applied biological sciences. Psychology; General aspects. Genetic counseling; Genetics of eukaryotes. Biological and molecular evolution; Headache. Facial pains. Syncopes. Epilepsia. Intracranial hypertension. Brain oedema. Cerebral palsy; Humans; Infant; Medical genetics; Medical sciences; Mice; Molecular and cellular biology; Molecular Sequence Data; Myelin Sheath - metabolism; Nervous system (semeiology, syndromes); Neurology; Phenotype; Quadriplegia - genetics; Spasms, Infantile - genetics; Spectrin - genetics; Transfection; Human; Spectrin; Tetraplegia; Nervous system diseases; Motor system disorder; Epilepsy; Developmental disorder; Cerebral disorder; Encephalon; West syndrome; Central nervous system disease; Genetics; Dominant character; Mutation; Neurological disorder; Severe
• ISSN: 0002-9297; 1537-6605; 1537-6605
• DOI: 10.1016/j.ajhg.2010.04.013

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 α-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 α/β 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) α-II spectrin could assemble heterodimers with β-II spectrin, but α-II (mut)/β-II spectrin heterodimers were thermolabile compared with the α-II (WT)/β-II heterodimers. Transient expression in mouse cortical neurons revealed aggregation of α-II (mut)/β-II and α-II (mut)/β-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 α/β spectrin heterodimers and abnormal AIS integrity resulting from SPTAN1 mutations were involved in pathogenesis of infantile epilepsy.