A novel SYN1 missense mutation in non-syndromic X-linked intellectual disability affects synaptic vesicle life cycle, clustering and mobility

Guarnieri, Fabrizia C.; Pozzi, Davide; Raimondi, Andrea; Fesce, Riccardo; Valente, Maria Giovanna; Delvecchio, Vincenza S; Esch, Hilde Van; Matteoli, Michela; Benfenati, Fabio; D’Adamo, Patrizia; Valtorta, Flavia

doi:10.1093/hmg/ddx352

Cited by 45 publications

(46 citation statements)

References 51 publications

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“…Therefore, we infer that different types of mutations cause different phenotypes, with truncating variants having an effect on firing/ bursting activity, as suggested by functional studies. 6,7 In conclusion, our update expands the phenotype of SYN1-related disorders, which represent a unique and recognizable condition. Epilepsy triggered by contact with water is a new and exciting area of research, and we encourage colleagues to test patients with this distinctive phenotype for SYN1 mutations, to clarify the hypotheses raised by our commentary.…”

Section: Hot Water Epilepsy and Syn1 Variantsmentioning

confidence: 72%

Hot water epilepsy and SYN1 variants

et al. 2018

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To the Editors: We read with great interest the article "X-Linked Focal Epilepsy With Reflex Bathing Seizures: Characterization of a Distinct Epileptic Syndrome" by Nguyen et al. 1 The authors described several males from a large family with focal reflex seizures triggered by contact with water, learning disabilities and/or autism, and a nonsense pathogenic variant in SYN1 (Xp11.3-p11.2).We had previously characterized the electroclinical manifestations of a family affected by childhood onset hot water epilepsy (HWE), subsequently followed by nonreflex seizures. 2 The proband presented with focal seizures during contact with water at age 8 years. The episodes-occurring especially after hot water had been poured on his bodywere characterized by a sensation of rising heat, dystonic posture of unilateral limbs, and cyanosis of the lips, followed by oral automatisms and inability to speak. Ictal electroencephalography (EEG) was characterized by bilateral rhythmic theta activity over the frontocentral and vertex regions. Three years after seizure onset, he exhibited nonreflex seizures consisting of a tingling ascending sensation starting from the lower limbs. His maternal uncle showed the same epileptic phenotype. Despite normal but below average intelligence quotient (80), the proband showed learning disability involving reading, writing, and calculation, and his maternal uncle exhibited mild intellectual disability (ID).We recently performed whole exome sequencing (WES) in this family and identified a splice-site pathogenic variant in SYN1 (NM_133499.2: c.527+1G>T). This variant segregates with the disease (present in proband, mother, and maternal uncle, absent in father; Figure 1) and is absent from the ExAc browser, ClinVar, and 1000 Genomes. Analysis of the splice donor mutation (GCGgtgagt to GCGttgagt) using the Human Splice Finder tool (http://www.umd.be/HSF3/, PMID 1933 9519) revealed a significant decrease in donor site score from 92% to 66% (position weight matrix algorithm) and the potential preference of a cryptic donor site five nucleotides upstream (GTCgtgcgt), thus leading to a shift in the reading frame. Prior testing of SCN1A produced normal results, 2 and WES did not identify other pathogenic or likely pathogenic variants affecting genes that have been previously associated with epilepsy/seizures in humans or mice.The pathogenesis of reflex seizures caused by contact with water is largely unknown, with proposed loci on chromosomes 4 and 10 1 and a family with a variant in SLC1A1 3 that was, however, present at a low frequency in the general population.

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Section: Hot Water Epilepsy and Syn1 Variantsmentioning

confidence: 72%

Hot water epilepsy and SYN1 variants

et al. 2018

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“…Previous studies reported that neuronal and synaptic loss in the cortex and hippocampus correlated best with cognitive dysfunction in AD, indicating that it is important in the pathogenesis [ 32 , 33 , 52 ]. The synapse-associated proteins, especially pre-synaptic Syn and post-synaptic PSD-95, play an important role in synaptic plasticity and memory formation [ 53 – 55 ]. It has been shown that pro-inflammatory cytokines are responsible for neuronal and synaptic loss, whereas anti-neuroinflammatory therapies may effectively attenuate synaptic damage and improve cognitive deficits [ 56 ].…”

Section: Discussionmentioning

confidence: 99%

Tanshinone IIA attenuates neuroinflammation via inhibiting RAGE/NF-κB signaling pathway in vivo and in vitro

Ding

Lin

Liu

et al. 2020

J Neuroinflammation

114

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Background Glial activation and neuroinflammation play a crucial role in the pathogenesis and development of Alzheimer’s disease (AD). The receptor for advanced glycation end products (RAGE)-mediated signaling pathway is related to amyloid beta (Aβ)-induced neuroinflammation. This study aimed to investigate the neuroprotective effects of tanshinone IIA (tan IIA), a natural product isolated from traditional Chinese herbal Salvia miltiorrhiza Bunge, against Aβ-induced neuroinflammation, cognitive impairment, and neurotoxicity as well as the underlying mechanisms in vivo and in vitro. Methods Open-field test, Y-maze test, and Morris water maze test were conducted to assess the cognitive function in APP/PS1 mice. Immunohistochemistry, immunofluorescence, thioflavin S (Th-S) staining, enzyme-linked immunosorbent assay (ELISA), real-time quantitative reverse-transcription polymerase chain reaction (qRT-PCR), and western blotting were performed to explore Aβ deposition, synaptic and neuronal loss, microglial and astrocytic activation, RAGE-dependent signaling, and the production of pro-inflammatory cytokines in APP/PS1 mice and cultured BV2 and U87 cells. Results Tan IIA treatment prevented spatial learning and memory deficits in APP/PS1 mice. Additionally, tan IIA attenuated Aβ accumulation, synapse-associated proteins (Syn and PSD-95) and neuronal loss, as well as peri-plaque microgliosis and astrocytosis in the cortex and hippocampus of APP/PS1 mice. Furthermore, tan IIA significantly suppressed RAGE/nuclear factor-κB (NF-κB) signaling pathway and the production of pro-inflammatory cytokines (TNF-α, IL-6, and IL-1β) in APP/PS1 mice and cultured BV2 and U87 cells. Conclusions Taken together, the present results indicated that tan IIA improves cognitive decline and neuroinflammation partly via inhibiting RAGE/NF-κB signaling pathway in vivo and in vitro. Thus, tan IIA might be a promising therapeutic drug for halting and preventing AD progression.

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“…Immunofluorescence experiments were performed as previously described 21 . Briefly, cells were rinsed once with phosphate buffer saline (PBS; Gibco #14200-056) for cells lines or Krebs-Ringer's solution (KRH)-EGTA (in mM: 130 NaCl, 5 KCl, 1.2 KH 2 PO 4 , 1.2 MgSO 4 , 2 MgCl 2 , 2 EGTA, 25 HEPES and 6 glucose, pH 7.4) for neurons.…”

Section: Cell Labelling Protocols and Image Acquisitionmentioning

confidence: 99%

Proline-rich transmembrane protein 2 (PRRT2) regulates the actin cytoskeleton during synaptogenesis

et al. 2020

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Mutations in proline-rich transmembrane protein 2 (PRRT2) have been recently identified as the leading cause of a clinically heterogeneous group of neurological disorders sharing a paroxysmal nature, including paroxysmal kinesigenic dyskinesia and benign familial infantile seizures. To date, studies aimed at understanding its physiological functions in neurons have mainly focused on its ability to regulate neurotransmitter release and neuronal excitability. Here, we show that PRRT2 expression in non-neuronal cell lines inhibits cell motility and focal adhesion turnover, increases cell aggregation propensity, and promotes the protrusion of filopodia, all processes impinging on the actin cytoskeleton. In primary hippocampal neurons, PRRT2 silencing affects the synaptic content of filamentous actin and perturbs actin dynamics. This is accompanied by defects in the density and maturation of dendritic spines. We identified cofilin, an actin-binding protein abundantly expressed at the synaptic level, as the ultimate effector of PRRT2. Indeed, PRRT2 silencing unbalances cofilin activity leading to the formation of cofilin-actin rods along neurites. The expression of a cofilin phospho-mimetic mutant (cof-S3E) is able to rescue PRRT2-dependent defects in synapse density, spine number and morphology, but not the alterations observed in neurotransmitter release. Our data support a novel function of PRRT2 in the regulation of the synaptic actin cytoskeleton and in the formation of synaptic contacts.

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A novel SYN1 missense mutation in non-syndromic X-linked intellectual disability affects synaptic vesicle life cycle, clustering and mobility

Cited by 45 publications

References 51 publications

Hot water epilepsy and SYN1 variants

Hot water epilepsy and SYN1 variants

Tanshinone IIA attenuates neuroinflammation via inhibiting RAGE/NF-κB signaling pathway in vivo and in vitro

Proline-rich transmembrane protein 2 (PRRT2) regulates the actin cytoskeleton during synaptogenesis

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