<i>STXBP1</i> mutations in early infantile epileptic encephalopathy with suppression‐burst pattern

Saitsu, Hirotomo; Kato, Mitsuhiro; Okada, Ippei; Orii, Kenji E.; Higuchi, Tsukasa; Hoshino, Hideki; Kubota, Masaya; Arai, Hiroshi; Tagawa, Tetsuzo; Kimura, Shigeru; Sudo, Akira; Miyama, Sahoko; Takami, Yuichi; Watanabe, Toshihide; Nishimura, Akira; Nishiyama, Kiyomi; Miyake, Noriko; Wada, Takahito; Osaka, Hitoshi; Kondo, Naomi; Hayasaka, Kiyoshi; Matsumoto, Naomichi

doi:10.1111/j.1528-1167.2010.02728.x

Cited by 139 publications

(145 citation statements)

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“…35,41,42 Six patients showed deletion of both SPTAN1 and STXBP1, 8,[36][37][38][39] and clinical features closely resemble those of STXBP1-mutated patients with Ohtahara syndrome or West syndrome. 8,37,43 In contrast, three patients had SPTAN1 deletion but intact STXBP1. 36,40 Figure 1 Brain MRI of subjects with SPTAN1 mutations.…”

Section: Role Of Spectrinsmentioning

confidence: 75%

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SPTAN1 encephalopathy: distinct phenotypes and genotypes

et al. 2015

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Recent progress in genetic analysis reveals that a significant proportion of cryptogenic epileptic encephalopathies are single-gene disorders. Mutations in numerous genes for early-onset epileptic encephalopathies have been rapidly identified, including in SPTAN1, which encodes α-II spectrin. The aim of this review is to delineate SPTAN1 encephalopathy as a distinct clinical syndrome. To date, a total of seven epileptic patients with four different in-frame SPTAN1 mutations have been identified. The major clinical features of SPTAN1 mutations include epileptic encephalopathy with hypsarrhythmia, no visual attention, acquired microcephaly, spastic quadriplegia and severe intellectual disability. Brainstem and cerebellar atrophy and cerebral hypomyelination, as observed by magnetic resonance imaging, are specific hallmarks of this condition. A milder variant is characterized by generalized epilepsy with pontocerebellar atrophy. Only in-frame SPTAN1 mutations in the last two spectrin repeats in the C-terminal region lead to dominant negative effects and these specific phenotypes. The last two spectrin repeats are required for α/β spectrin heterodimer associations and the mutations can alter heterodimer formation between the two spectrins. From these data we suggest that SPTAN1 encephalopathy is a distinct clinical syndrome owing to specific SPTAN1 mutations. It is important that this syndrome is recognized by pediatric neurologists to enable proper diagnostic work-up for patients.

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Section: Role Of Spectrinsmentioning

confidence: 75%

“…In patients with STXBP1 mutations, delayed myelination in the cerebrum is observed. 8,43,48 MRI shows that patients with STXBP1 mutations do not usually involve brainstem and cerebellum, whereas those with SPTAN1 encephalopathy show brainstem and cerebellum atrophy.…”

Section: Role Of Spectrinsmentioning

confidence: 97%

SPTAN1 encephalopathy: distinct phenotypes and genotypes

et al. 2015

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“…Of the .50 patients with STXBP1 encephalopathy described, the majority present by 3 months of age, with Ohtahara syndrome or other early-onset epileptic encephalopathies. [22][23][24][25][26][27][28][29][30][31][32] Our patients had onset from 6 to 12 months, which is later than usually seen in STXBP1 encephalopathy. It is typically associated with epileptic spasms, and notably these were not observed in our patients with Dravet syndrome.…”

Section: 16mentioning

confidence: 99%

GABRA1 and STXBP1 : Novel genetic causes of Dravet syndrome

et al. 2014

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Objective: To determine the genes underlying Dravet syndrome in patients who do not have an SCN1A mutation on routine testing. Methods:We performed whole-exome sequencing in 13 SCN1A-negative patients with Dravet syndrome and targeted resequencing in 67 additional patients to identify new genes for this disorder.Results: We detected disease-causing mutations in 2 novel genes for Dravet syndrome, with mutations in GABRA1 in 4 cases and STXBP1 in 3. Furthermore, we identified 3 patients with previously undetected SCN1A mutations, suggesting that SCN1A mutations occur in even more than the currently accepted ;75% of cases. Conclusions:We show that GABRA1 and STXBP1 make a significant contribution to Dravet syndrome after SCN1A abnormalities have been excluded. Our results have important implications for diagnostic testing, clinical management, and genetic counseling of patients with this devastating disorder and their families. Neurology ® 2014;82:1245-1253 GLOSSARY cDNA 5 complementary DNA; dHPLC 5 denaturing high-performance liquid chromatography; FS 5 febrile seizures; GABA 5 g-aminobutyric acid; GEFS1 5 genetic epilepsy with febrile seizures plus; WES 5 whole-exome sequencing; WT 5 wild-type.

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“…However, a recent NMR study on full length Sx1a, including its TMD, reported a higher proportion of the open Sx1a conformation than was observed using the soluble cytosolic domain of Sx1a (Dawidowski & Cafiso, 2013 Although its precise role remains controversial, the importance of SM proteins in disease has been well documented. For example, mutations in Munc18a have been linked with early infantile epileptic encephalopathy (Saitsu et al, 2008(Saitsu et al, , 2010 and Munc18b mutations can result in familial hemophagocytic lymphohistiocytosis type 5 (Cô te et al, 2009;Hackmann et al, 2013). This link between SM proteins and disease has also been confirmed by mutagenesis studies in mice, where deletion of Munc18-1 in mice leads to a complete loss of neurotransmitter secretion from synaptic vesicles throughout development (Verhage et al, 2000).…”

Section: Introductionmentioning

confidence: 53%

Reconciling the regulatory role of Munc18 proteins in SNARE-complex assembly

Rehman

Archbold

et al. 2014

Int Union Crystallogr J

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Membrane fusion is essential for human health, playing a vital role in processes as diverse as neurotransmission and blood glucose control. Two protein families are key: (1) the Sec1p/Munc18 (SM) and (2) the soluble N-ethylmaleimidesensitive attachment protein receptor (SNARE) proteins. Whilst the essential nature of these proteins is irrefutable, their exact regulatory roles in membrane fusion remain controversial. In particular, whether SM proteins promote and/or inhibit the SNARE-complex formation required for membrane fusion is not resolved. Crystal structures of SM proteins alone and in complex with their cognate SNARE proteins have provided some insight, however, these structures lack the transmembrane spanning regions of the SNARE proteins and may not accurately reflect the native state. Here, we review the literature surrounding the regulatory role of mammalian Munc18 SM proteins required for exocytosis in eukaryotes. Our analysis suggests that the conflicting roles reported for these SM proteins may reflect differences in experimental design. SNARE proteins appear to require C-terminal immobilization or anchoring, for example through a transmembrane domain, to form a functional fusion complex in the presence of Munc18 proteins.

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STXBP1 mutations in early infantile epileptic encephalopathy with suppression‐burst pattern

Abstract: 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.

Cited by 139 publications

References 19 publications

SPTAN1 encephalopathy: distinct phenotypes and genotypes

SPTAN1 encephalopathy: distinct phenotypes and genotypes

GABRA1 and STXBP1 : Novel genetic causes of Dravet syndrome

Reconciling the regulatory role of Munc18 proteins in SNARE-complex assembly

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