scholarly journals Heterozygous variants in the mechanosensitive ion channelTMEM63Aresult in transient hypomyelination during infancy

2019 ◽  
Author(s):  
Huifang Yan ◽  
Guy Helman ◽  
Swetha E. Murthy ◽  
Haoran Ji ◽  
Joanna Crawford ◽  
...  
Keyword(s):  
Ion Channels ◽  
Ion Channel ◽  
De Novo ◽  
Physiological Role ◽  
Congenital Nystagmus ◽  
Missense Mutations ◽  
Gene Encoding ◽  
Motor Delay ◽  
Mechanosensitive Ion Channels ◽  
Patch Clamp Electrophysiology

Mechanically activated (MA) ion channels convert physical forces into electrical signals. Despite the importance of this function, the involvement of mechanosensitive ion channels in human disease is poorly understood. Here we report heterozygous missense mutations in the gene encoding the MA ion channel TMEM63A that result in an infantile disorder resembling a hypomyelinating leukodystrophy. Four unrelated individuals presented with congenital nystagmus, motor delay, and deficient myelination on serial scans in infancy, prompting the diagnosis of Pelizaeus-Merzbacher (like) disease. Genomic sequencing revealed all four individuals carry heterozygous missense variants in the pore-forming domain of TMEM63A. These variants were confirmed to have arisende novoin three of the four individuals. While the physiological role of TMEM63A is incompletely understood, it is highly expressed in oligodendrocytes and it has recently been shown to be a mechanically activated (MA) ion channel. Using patch clamp electrophysiology, we demonstrated that each of the modelled variants results in strongly attenuated stretch-activated currents when expressed in naïve cells. Unexpectedly, the clinical evolution of all four individuals has been surprisingly favorable, with substantial improvements in neurological signs and developmental progression. In the three individuals with follow-up scans after four years of age, the myelin deficit had almost completely resolved. Our results suggest a previously unappreciated role for mechanosensitive ion channels in myelin development.

scholarly journals PIEZO ion channel is required for root mechanotransduction in Arabidopsis thaliana

2020 ◽  
Author(s):  
Seyed A. R. Mousavi ◽  
Adrienne E Dubin ◽  
Wei-Zheng Zeng ◽  
Adam M. Coombs ◽  
Khai Do ◽  
...  
Keyword(s):  
Arabidopsis Thaliana ◽  
Ion Channels ◽  
Ion Channel ◽  
Mammalian Cells ◽  
Plant Root ◽  
Mechanical Strain ◽  
Root Tip ◽  
Root Tips ◽  
Mechanosensitive Ion Channels ◽  
Mechanical Constraints

SummaryPlant roots adapt to the mechanical constraints of the soil to grow and absorb water and nutrients. As in animal species, mechanosensitive ion channels in plants are proposed to transduce external mechanical forces into biological signals. However, the identity of these plant root ion channels remains unknown. Here, we show that Arabidopsis thaliana PIEZO (AtPIEZO) has preserved the function of its animal relatives and acts as an ion channel. We present evidence that plant PIEZO is highly expressed in the columella and lateral root cap cells of the root tip which experience robust mechanical strain during root growth. Deleting PIEZO from the whole plant significantly reduced the ability of its roots to penetrate denser barriers compared to wild type plants. piezo mutant root tips exhibited diminished calcium transients in response to mechanical stimulation, supporting a role of AtPIEZO in root mechanotransduction. Finally, a chimeric PIEZO channel that includes the C-terminal half of AtPIEZO containing the putative pore region was functional and mechanosensitive when expressed in naive mammalian cells. Collectively, our data suggest that Arabidopsis PIEZO plays an important role in root mechanotransduction and establishes PIEZOs as physiologically relevant mechanosensitive ion channels across animal and plant kingdoms.

scholarly journals De novo SCN8A and inherited rare CACNA1H variants associated with severe developmental and epileptic encephalopathy

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Robin N. Stringer ◽  
Bohumila Jurkovicova-Tarabova ◽  
Ivana A. Souza ◽  
Judy Ibrahim ◽  
Tomas Vacik ◽  
...  
Keyword(s):  
Ion Channel ◽  
De Novo ◽  
Epileptic Encephalopathy ◽  
Gene Encoding ◽  
Epileptic Encephalopathies ◽  
Voltage Gated ◽  
Voltage Gated Calcium Channels ◽  
Whole Exome ◽  
Heterozygous Variant

AbstractDevelopmental and epileptic encephalopathies (DEEs) are a group of severe epilepsies that are characterized by seizures and developmental delay. DEEs are primarily attributed to genetic causes and an increasing number of cases have been correlated with variants in ion channel genes. In this study, we report a child with an early severe DEE. Whole exome sequencing showed a de novo heterozygous variant (c.4873–4881 duplication) in the SCN8A gene and an inherited heterozygous variant (c.952G > A) in the CACNA1H gene encoding for Nav1.6 voltage-gated sodium and Cav3.2 voltage-gated calcium channels, respectively. In vitro functional analysis of human Nav1.6 and Cav3.2 channel variants revealed mild but significant alterations of their gating properties that were in general consistent with a gain- and loss-of-channel function, respectively. Although additional studies will be required to confirm the actual pathogenic involvement of SCN8A and CACNA1H, these findings add to the notion that rare ion channel variants may contribute to the etiology of DEEs.

scholarly journals Naked mole-rat acid-sensing ion channel 3 forms nonfunctional homomers, but functional heteromers

2017 ◽  
Author(s):  
Laura-Nadine Schuhmacher ◽  
Gerard Callejo ◽  
Shyam Srivats ◽  
Ewan St. John Smith
Keyword(s):  
Carbon Dioxide ◽  
Ion Channels ◽  
Ion Channel ◽  
Drg Neurons ◽  
Whole Cell Patch Clamp ◽  
Mole Rat ◽  
Wide Range ◽  
Naked Mole Rat ◽  
Patch Clamp Electrophysiology ◽  
Carbon Dioxide Levels

ABSTRACTAcid-sensing ion channels (ASICs) form both homotrimeric and heterotrimeric ion channels that are activated by extracellular protons and are involved in a wide range of physiological and pathophysiological processes, including pain and anxiety. ASIC proteins can form both homotrimeric and heterotrimeric ion channels. The ASIC3 subunit has been shown to be of particular importance in the peripheral nervous system with pharmacological and genetic manipulations demonstrating a role in pain. Naked mole-rats, despite having functional ASICs, are insensitive to acid as a noxious stimulus and show diminished avoidance of acidic fumes, ammonia and carbon dioxide. Here we cloned naked mole-rat ASIC3 (nmrASIC3) and used a cell surface biotinylation assay to demonstrate that it traffics to the plasma membrane, but using whole-cell patch-clamp electrophysiology we observed that nmrASIC3 is insensitive to both protons and the non-proton ASIC3 agonist 2-Guanidine-4-methylquinazoline (GMQ). However, in line with previous reports of ASIC3 mRNA expression in dorsal root ganglia (DRG) neurons, we found that the ASIC3 antagonist APETx2 reversibly inhibits ASIC-like currents in naked mole-rat DRG neurons. We further show that like the proton-insensitive ASIC2b and ASIC4, nmrASIC3 forms functional, proton sensitive heteromers with other ASIC subunits. An amino acid alignment of ASIC3s between 9 relevant rodent species and human identified unique sequence differences that might underlie the proton insensitivity of nmrASIC3. However, introducing nmrASIC3 differences into rat ASIC3 (rASIC3) produced only minor differences in channel function, and replacing nmrASIC3 sequence with that of rASIC3 did not produce a proton-sensitive ion channel. Our observation that nmrASIC3 forms nonfunctional homomers may reflect a further adaptation of the naked mole-rat to living in an environment with high-carbon dioxide levels.

scholarly journals Abnormal myocardial expression of SAP97 is associated with arrhythmogenic risk

2020 ◽  
Vol 318 (6) ◽  
pp. H1357-H1370
Author(s):  
Hassan Musa ◽  
Cherisse A. Marcou ◽  
Todd J. Herron ◽  
Michael A. Makara ◽  
David J. Tester ◽  
...  
Keyword(s):  
Ion Channels ◽  
Ion Channel ◽  
Brugada Syndrome ◽  
Susceptibility Gene ◽  
Susceptibility Genes ◽  
Interacting Proteins ◽  
Gene Encoding ◽  
Electrical Impulse ◽  
Genes Encoding ◽  
A Minor

The gene encoding SAP97 ( DLG1) joins a growing list of genes encoding ion channel interacting proteins (ChIPs) identified as potential channelopathy-susceptibility genes because of their ability to regulate the trafficking, targeting, and modulation of ion channels that are critical for the generation and propagation of the cardiac electrical impulse. In this study we provide the first data supporting DLG1-encoded SAP97’s candidacy as a minor Brugada syndrome susceptibility gene.

scholarly journals The L1624Q Variant in SCN1A Causes Familial Epilepsy Through a Mixed Gain and Loss of Channel Function

2021 ◽  
Vol 12 ◽  
Author(s):  
Laura B. Jones ◽  
Colin H. Peters ◽  
Richard E. Rosch ◽  
Maxine Owers ◽  
Elaine Hughes ◽  
...  
Keyword(s):  
De Novo ◽  
Epileptic Encephalopathy ◽  
Dravet Syndrome ◽  
Missense Mutations ◽  
Loss Of Function ◽  
Gene Encoding ◽  
Channel Function ◽  
Biophysical Analysis ◽  
Gain And Loss ◽  
Patients With Epilepsy

Variants of the SCN1A gene encoding the neuronal voltage-gated sodium channel NaV1.1 cause over 85% of all cases of Dravet syndrome, a severe and often pharmacoresistent epileptic encephalopathy with mostly infantile onset. But with the increased availability of genetic testing for patients with epilepsy, variants in SCN1A have now also been described in a range of other epilepsy phenotypes. The vast majority of these epilepsy-associated variants are de novo, and most are either nonsense variants that truncate the channel or missense variants that are presumed to cause loss of channel function. However, biophysical analysis has revealed a significant subset of missense mutations that result in increased excitability, further complicating approaches to precision pharmacotherapy for patients with SCN1A variants and epilepsy. We describe clinical and biophysical data of a familial SCN1A variant encoding the NaV1.1 L1624Q mutant. This substitution is located on the extracellular linker between S3 and S4 of Domain IV of NaV1.1 and is a rare case of a familial SCN1A variant causing an autosomal dominant frontal lobe epilepsy. We expressed wild-type (WT) and L1642Q channels in CHO cells. Using patch-clamp to characterize channel properties at several temperatures, we show that the L1624Q variant increases persistent current, accelerates fast inactivation onset and decreases current density. While SCN1A-associated epilepsy is typically considered a loss-of-function disease, our results put L1624Q into a growing set of mixed gain and loss-of-function variants in SCN1A responsible for epilepsy.

Whole Exon Deletion in the GFAP Gene Is a Novel Molecular Mechanism Causing Alexander Disease

2017 ◽  
Vol 49 (02) ◽  
pp. 118-122 ◽  
Author(s):  
Lydia Green ◽  
Ian Berry ◽  
Anne-Marie Childs ◽  
Helen McCullagh ◽  
Sandhya Jose ◽  
...  
Keyword(s):  
De Novo ◽  
Mutation Screening ◽  
Copy Number Variants ◽  
Gene Mutations ◽  
Fiber Formation ◽  
Alexander Disease ◽  
Missense Mutations ◽  
Gene Encoding ◽  
Whole Exome ◽  
Filament Network

AbstractAlexander disease (AD) is a leukodystrophy caused by heterozygous mutations in the gene encoding the glial fibrillary acidic protein (GFAP). Currently, de novo heterozygous missense mutations in the GFAP gene are identified in over 95% of patients with AD. However, patients with biopsy-proven AD have been reported in whom no GFAP mutation has been identified. We report identical twin boys presenting in infancy with seizures and developmental delay in whom MR appearances were suggestive of AD with the exception of an unusual, bilateral, arc of calcification at the frontal white–gray junction. Initial mutation screening of the GFAP gene did not identify a mutation. Whole exome sequencing in both brothers revealed a de novo heterozygous in-frame deletion of the whole of exon 5 of the GFAP gene. Mutations in the GFAP gene are thought to result in a toxic effect of mutant GFAP disrupting the formation of the normal intermediate filament network and resulting in Rosenthal fiber formation, which has hitherto not been linked to exonic scale copy number variants in GFAP. Further studies on mutation negative AD patients are warranted to determine whether a similar mechanism underlies their disease.

scholarly journals Selective activation of mechanosensitive ion channels using magnetic particles

2007 ◽  
Vol 5 (25) ◽  
pp. 855-863 ◽  
Author(s):  
Steven Hughes ◽  
Stuart McBain ◽  
Jon Dobson ◽  
Alicia J El Haj
Keyword(s):  
Ion Channels ◽  
Ion Channel ◽  
Magnetic Particles ◽  
Channel Structure ◽  
Biological Research ◽  
Mechanical Forces ◽  
Extracellular Loop ◽  
Whole Cell ◽  
Mechanosensitive Ion Channels ◽  
Loop Region

This study reports the preliminary development of a novel magnetic particle-based technique that permits the application of highly localized mechanical forces directly to specific regions of an ion-channel structure. We demonstrate that this approach can be used to directly and selectively activate a mechanosensitive ion channel of interest, namely TREK-1. It is shown that manipulation of particles targeted against the extended extracellular loop region of TREK-1 leads to changes in whole-cell currents consistent with changes in TREK-1 activity. Responses were absent when particles were coated with RGD (Arg–Gly–Asp) peptide or when magnetic fields were applied in the absence of magnetic particles. It is concluded that changes in whole-cell current are the result of direct force application to the extracellular loop region of TREK-1 and thus these results implicate this region of the channel structure in mechano-gating. It is hypothesized that the extended loop region of TREK-1 may act as a tension spring that acts to regulate sensitivity to mechanical forces, in a nature similar to that described for MscL. The development of a technique that permits the direct manipulation of mechanosensitive ion channels in real time without the need for pharmacological drugs has huge potential benefits not only for basic biological research of ion-channel gating mechanisms, but also potentially as a tool for the treatment of human diseases caused by ion-channel dysfunction.

scholarly journals PIEZO ion channel is required for root mechanotransduction in Arabidopsis thaliana

2021 ◽  
Vol 118 (20) ◽  
pp. e2102188118
Author(s):  
Seyed A. R. Mousavi ◽  
Adrienne E. Dubin ◽  
Wei-Zheng Zeng ◽  
Adam M. Coombs ◽  
Khai Do ◽  
...  
Keyword(s):  
Arabidopsis Thaliana ◽  
Ion Channels ◽  
Ion Channel ◽  
Mammalian Cells ◽  
Plant Root ◽  
Mechanical Strain ◽  
Root Tip ◽  
Root Tips ◽  
Mechanosensitive Ion Channels ◽  
Mechanical Constraints

Plant roots adapt to the mechanical constraints of the soil to grow and absorb water and nutrients. As in animal species, mechanosensitive ion channels in plants are proposed to transduce external mechanical forces into biological signals. However, the identity of these plant root ion channels remains unknown. Here, we show that Arabidopsis thaliana PIEZO1 (PZO1) has preserved the function of its animal relatives and acts as an ion channel. We present evidence that plant PIEZO1 is expressed in the columella and lateral root cap cells of the root tip, which are known to experience robust mechanical strain during root growth. Deleting PZO1 from the whole plant significantly reduced the ability of its roots to penetrate denser barriers compared to wild-type plants. pzo1 mutant root tips exhibited diminished calcium transients in response to mechanical stimulation, supporting a role of PZO1 in root mechanotransduction. Finally, a chimeric PZO1 channel that includes the C-terminal half of PZO1 containing the putative pore region was functional and mechanosensitive when expressed in naive mammalian cells. Collectively, our data suggest that Arabidopsis PIEZO1 plays an important role in root mechanotransduction and establish PIEZOs as physiologically relevant mechanosensitive ion channels across animal and plant kingdoms.

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