Haploinsufficiency of the STX1B gene is associated with myoclonic astatic epilepsy

Vlaskamp, Danique R.M.; Rump, Patricia; Callenbach, Petra M. C.; Vos, Yvonne J.; Sikkema‐Raddatz, Birgit; Ravenswaaij-Arts, Conny M. A. van; Brouwer, Oebele F.

doi:10.1016/j.ejpn.2015.12.014

Cited by 38 publications

(29 citation statements)

References 13 publications

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“…Syntaxin-1 is well-characterized as a presynaptic protein that regulates neurotransmitter release; however, its function postsynaptically remains unclear (Bennett et al, 1992, 1993; Rizo and Südhof, 2002, 2012; Rizo and Xu, 2015). Contrary to earlier assumptions, recent studies now reveal that presynaptic syntaxin-1A and 1B perform distinct roles (Mishima et al, 2014; Schubert et al, 2014; Vlaskamp et al, 2016). In light of these findings, we propose that syntaxin-1A and syntaxin-1B perform different roles in mediating mTORC1-dependent regulation of postsynaptic membrane potential as described below.…”

Section: Mtorc1-mediated Negative Feedback Regulation Of the Postsynamentioning

confidence: 82%

mTORC1 Is a Local, Postsynaptic Voltage Sensor Regulated by Positive and Negative Feedback Pathways

Niere

Raab‐Graham

2017

Front. Cell. Neurosci.

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The mammalian/mechanistic target of rapamycin complex 1 (mTORC1) serves as a regulator of mRNA translation. Recent studies suggest that mTORC1 may also serve as a local, voltage sensor in the postsynaptic region of neurons. Considering biochemical, bioinformatics and imaging data, we hypothesize that the activity state of mTORC1 dynamically regulates local membrane potential by promoting and repressing protein synthesis of select mRNAs. Our hypothesis suggests that mTORC1 uses positive and negative feedback pathways, in a branch-specific manner, to maintain neuronal excitability within an optimal range. In some dendritic branches, mTORC1 activity oscillates between the “On” and “Off” states. We define this as negative feedback. In contrast, positive feedback is defined as the pathway that leads to a prolonged depolarized or hyperpolarized resting membrane potential, whereby mTORC1 activity is constitutively on or off, respectively. We propose that inactivation of mTORC1 increases the expression of voltage-gated potassium alpha (Kv1.1 and 1.2) and beta (Kvβ2) subunits, ensuring that the membrane resets to its resting membrane potential after experiencing increased synaptic activity. In turn, reduced mTORC1 activity increases the protein expression of syntaxin-1A and promotes the surface expression of the ionotropic glutamate receptor N-methyl-D-aspartate (NMDA)-type subunit 1 (GluN1) that facilitates increased calcium entry to turn mTORC1 back on. Under conditions such as learning and memory, mTORC1 activity is required to be high for longer periods of time. Thus, the arm of the pathway that promotes syntaxin-1A and Kv1 protein synthesis will be repressed. Moreover, dendritic branches that have low mTORC1 activity with increased Kv expression would balance dendrites with constitutively high mTORC1 activity, allowing for the neuron to maintain its overall activity level within an ideal operating range. Finally, such a model suggests that recruitment of more positive feedback dendritic branches within a neuron is likely to lead to neurodegenerative disorders.

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Section: Mtorc1-mediated Negative Feedback Regulation Of the Postsynamentioning

confidence: 82%

mTORC1 Is a Local, Postsynaptic Voltage Sensor Regulated by Positive and Negative Feedback Pathways

Niere

Raab‐Graham

2017

Front. Cell. Neurosci.

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“…Many proteins were decreased in CLN1 brain, but two of particular interest are STXBP1 and STX1B, which were both decreased to ∼0.4-fold of control levels, which is likely an underestimate of the actual decrease (see earlier comments above regarding reporter ion ratio compression). A recent report 47 indicates that haploinsufficiency for STX1B is associated with myoclonic epilepsy, while mutations in STXBP1 are associated with various neurodevelopmental disorders including epilepsy and intellectual disability. 48 The clinical phenotypes associated with STX1B and STXBP1 bear some similarity with NCL diseases, raising the intriguing possibility that, for CLN1 at least, disease may partly reflect decreased expression of these two proteins.…”

Section: Resultsmentioning

confidence: 99%

Proteomic Analysis of Brain and Cerebrospinal Fluid from the Three Major Forms of Neuronal Ceroid Lipofuscinosis Reveals Potential Biomarkers

Sleat

Tannous²,

Sohár³

et al. 2017

J. Proteome Res.

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Clinical trials have been conducted for the neuronal ceroid lipofuscinoses (NCLs), a group of neurodegenerative lysosomal diseases that primarily affect children. Whereas clinical rating systems will evaluate long-term efficacy, biomarkers to measure short-term response to treatment would be extremely valuable. To identify candidate biomarkers, we analyzed autopsy brain and matching CSF samples from controls and three genetically distinct NCLs due to deficiencies in palmitoyl protein thioesterase 1 (CLN1 disease), tripeptidyl peptidase 1 (CLN2 disease), and CLN3 protein (CLN3 disease). Proteomic and biochemical methods were used to analyze lysosomal proteins, and, in general, we find that changes in protein expression compared with control were most similar between CLN2 disease and CLN3 disease. This is consistent with previous observations of biochemical similarities between these diseases. We also conducted unbiased proteomic analyses of CSF and brain using isobaric labeling/quantitative mass spectrometry. Significant alterations in protein expression were identified in each NCL, including reduced STXBP1 in CLN1 disease brain. Given the confounding variable of post-mortem changes, additional validation is required, but this study provides a useful starting set of candidate NCL biomarkers for further evaluation.

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“…Inactivation of syntaxin 1B likely accounts for the patient's cortical hyperexcitability, because gene mutations of syntaxin 1B are associated with febrile seizures with or without epilepsy, 25 and haploinsufficiency of STX1B is associated with myoclonic astatic epilepsy. 26 A recent publication provides an explanation for our patient's microcephaly by showing that syntaxin 1B has an obligatory role in maintenance of developing or mature neurons and illustrates impaired brain development in syntaxin 1A/1B double gene knockout mice. 27 We therefore attribute our patient's microcephaly to the truncating homozygous Munc13-1 gene mutation that consigns syntaxin 1B to a permanently closed nonfunctional state akin to a knockout.…”

Section: Expression Studies (A) Mixing Liposomes Incorporating Wilmentioning

confidence: 85%

Section: Munc13‐1 Myastheniamentioning

confidence: 99%

The unfolding landscape of the congenital myasthenic syndromes

Engel

Shen

Selcen

2018

Annals of the New York Academy of Sciences

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Congenital myasthenic syndromes (CMS) are heterogeneous disorders in which the safety margin of neuromuscular transmission is impaired by one or more specific mechanisms. Since the advent of next-generation sequencing methods, the discovery of novel CMS targets and phenotypes has proceeded at an accelerated rate. Here, we review the current classification of CMS and describe our findings in five of these targets identified and investigated in our laboratory in the past 5 years. Defects in LRP4 hinder synaptic development and maintenance; the defects in PREPL are predicted to diminish filling of the synaptic vesicle with acetylcholine; and defects in SNAP25, Munc13-1, and synaptotbrevin-1 impede synaptic vesicle exocytosis.

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Haploinsufficiency of the STX1B gene is associated with myoclonic astatic epilepsy

Cited by 38 publications

References 13 publications

mTORC1 Is a Local, Postsynaptic Voltage Sensor Regulated by Positive and Negative Feedback Pathways

mTORC1 Is a Local, Postsynaptic Voltage Sensor Regulated by Positive and Negative Feedback Pathways

Proteomic Analysis of Brain and Cerebrospinal Fluid from the Three Major Forms of Neuronal Ceroid Lipofuscinosis Reveals Potential Biomarkers

The unfolding landscape of the congenital myasthenic syndromes

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