scholarly journals Novel Missense CACNA1G Mutations Associated with Infantile-Onset Developmental and Epileptic Encephalopathy

2020 ◽  
Vol 21 (17) ◽  
pp. 6333
Author(s):  
Géza Berecki ◽  
Katherine L. Helbig ◽  
Tyson L. Ware ◽  
Bronwyn Grinton ◽  
Cara M. Skraban ◽  
...  
Keyword(s):  
Mammalian Cells ◽  
Low Voltage ◽  
Cerebellar Atrophy ◽  
Epileptic Encephalopathy ◽  
Loss Of Function ◽  
Gain Of Function ◽  
Complex Phenotypes ◽  
Refractory Seizures ◽  
Kinetics Of ◽  
Hyperpolarizing Shift

The CACNA1G gene encodes the low-voltage-activated Cav3.1 channel, which is expressed in various areas of the CNS, including the cerebellum. We studied two missense CACNA1G variants, p.L208P and p.L909F, and evaluated the relationships between the severity of Cav3.1 dysfunction and the clinical phenotype. The presentation was of a developmental and epileptic encephalopathy without evident cerebellar atrophy. Both patients exhibited axial hypotonia, developmental delay, and severe to profound cognitive impairment. The patient with the L909F mutation had initially refractory seizures and cerebellar ataxia, whereas the L208P patient had seizures only transiently but was overall more severely affected. In transfected mammalian cells, we determined the biophysical characteristics of L208P and L909F variants, relative to the wild-type channel and a previously reported gain-of-function Cav3.1 variant. The L208P mutation shifted the activation and inactivation curves to the hyperpolarized direction, slowed the kinetics of inactivation and deactivation, and reduced the availability of Ca2+ current during repetitive stimuli. The L909F mutation impacted channel function less severely, resulting in a hyperpolarizing shift of the activation curve and slower deactivation. These data suggest that L909F results in gain-of-function, whereas L208P exhibits mixed gain-of-function and loss-of-function effects due to opposing changes in the biophysical properties. Our study expands the clinical spectrum associated with CACNA1G mutations, corroborating further the causal association with distinct complex phenotypes.

scholarly journals Potassium Channel Gain of Function in Epilepsy: An Unresolved Paradox

2018 ◽  
Vol 24 (4) ◽  
pp. 368-380 ◽  
Author(s):  
Zachary Niday ◽  
Anastasios V. Tzingounis
Keyword(s):  
Potassium Channel ◽  
Epileptic Encephalopathy ◽  
Channel Gain ◽  
Loss Of Function ◽  
Cellular Mechanisms ◽  
Gain Of Function ◽  
New Genes ◽  
Current State ◽  
Migrating Partial Seizures ◽  
Surprising Finding

Exome and targeted sequencing have revolutionized clinical diagnosis. This has been particularly striking in epilepsy and neurodevelopmental disorders, for which new genes or new variants of preexisting candidate genes are being continuously identified at increasing rates every year. A surprising finding of these efforts is the recognition that gain of function potassium channel variants are actually associated with certain types of epilepsy, such as malignant migrating partial seizures of infancy or early-onset epileptic encephalopathy. This development has been difficult to understand as traditionally potassium channel loss-of-function, not gain-of-function, has been associated with hyperexcitability disorders. In this article, we describe the current state of the field regarding the gain-of-function potassium channel variants associated with epilepsy (KCNA2, KCNB1, KCND2, KCNH1, KCNH5, KCNJ10, KCNMA1, KCNQ2, KCNQ3, and KCNT1) and speculate on the possible cellular mechanisms behind the development of seizures and epilepsy in these patients. Understanding how potassium channel gain-of-function leads to epilepsy will provide new insights into the inner working of neural circuits and aid in developing new therapies.

scholarly journals Gain-of-function FHF1 mutation causes early-onset epileptic encephalopathy with cerebellar atrophy

Neurology ◽  
2016 ◽  
Vol 86 (23) ◽  
pp. 2162-2170 ◽  
Author(s):  
Aleksandra Siekierska ◽  
Mala Isrie ◽  
Yue Liu ◽  
Chloë Scheldeman ◽  
Niels Vanthillo ◽  
...  
Keyword(s):  
Early Onset ◽  
Cerebellar Atrophy ◽  
Epileptic Encephalopathy ◽  
Gain Of Function

scholarly journals Loss–of–function variants in the KCNQ5 gene are associated with genetic generalized epilepsies

2021 ◽  
Author(s):  
Johanna Krueger ◽  
Julian Schubert ◽  
Josua Kegele ◽  
Audrey Labalme ◽  
Miaomiao Mao ◽  
...  
Keyword(s):  
Mammalian Cells ◽  
De Novo ◽  
Surface Expression ◽  
Epileptic Encephalopathy ◽  
Dominant Negative ◽  
Dominant Negative Effect ◽  
K Channel ◽  
Loss Of Function ◽  
Normal Surface ◽  
Missense Variants

Objective: De novo missense variants in KCNQ5, encoding the voltage–gated K+ channel KV7.5, have been described as a cause of developmental and epileptic encephalopathy (DEE) or intellectual disability (ID). We set out to identify disease–related KCNQ5 variants in genetic generalized epilepsy (GGE) and their underlying mechanisms. Methods: 1292 families with GGE were studied by next-generation sequencing. Whole–cell patch–clamp recordings, biotinylation and phospholipid overlay assays were performed in mammalian cells combined with docking and homology modeling. Results: We identified three deleterious heterozygous missense variants, one truncation and one splice site alteration in five independent families with GGE with predominant absence seizures, two variants were also associated with mild to moderate ID. All three missense variants displayed a strongly decreased current density indicating a loss–of–function (LOF). When mutant channels were co–expressed with wild–type (WT) KV7.5 or KV7.5 and KV7.3 channels, three variants also revealed a significant dominant–negative effect on WT channels. Other gating parameters were unchanged. Biotinylation assays indicated a normal surface expression of the variants. The p.Arg359Cys variant altered PI(4,5)P2–interaction, presumably in the non–conducting preopen–closed state. Interpretation: Our study indicates that specific deleterious KCNQ5 variants are associated with GGE, partially combined with mild to moderate ID. The disease mechanism is a LOF partially with dominant–negative effects through functional, rather than trafficking deficits. LOF of KV7.5 channels will reduce the M–current, likely resulting in increased excitability of KV7.5–expressing neurons. Further studies on a network level are necessary to understand which circuits are affected and how the variants induce generalized seizures.

scholarly journals Calcium channelopathies and intellectual disability: a systematic review

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Miriam Kessi ◽  
Baiyu Chen ◽  
Jing Peng ◽  
Fangling Yan ◽  
Lifen Yang ◽  
...  
Keyword(s):  
Systematic Review ◽  
Intellectual Disability ◽  
Calcium Channel ◽  
Developmental Delay ◽  
Cerebellar Atrophy ◽  
Dominant Negative ◽  
Main Body ◽  
Loss Of Function ◽  
Gain Of Function ◽  
Gain And Loss

Abstract Background Calcium ions are involved in several human cellular processes including corticogenesis, transcription, and synaptogenesis. Nevertheless, the relationship between calcium channelopathies (CCs) and intellectual disability (ID)/global developmental delay (GDD) has been poorly investigated. We hypothesised that CCs play a major role in the development of ID/GDD and that both gain- and loss-of-function variants of calcium channel genes can induce ID/GDD. As a result, we performed a systematic review to investigate the contribution of CCs, potential mechanisms underlying their involvement in ID/GDD, advancements in cell and animal models, treatments, brain anomalies in patients with CCs, and the existing gaps in the knowledge. We performed a systematic search in PubMed, Embase, ClinVar, OMIM, ClinGen, Gene Reviews, DECIPHER and LOVD databases to search for articles/records published before March 2021. The following search strategies were employed: ID and calcium channel, mental retardation and calcium channel, GDD and calcium channel, developmental delay and calcium channel. Main body A total of 59 reports describing 159 cases were found in PubMed, Embase, ClinVar, and LOVD databases. Variations in ten calcium channel genes including CACNA1A, CACNA1C, CACNA1I, CACNA1H, CACNA1D, CACNA2D1, CACNA2D2, CACNA1E, CACNA1F, and CACNA1G were found to be associated with ID/GDD. Most variants exhibited gain-of-function effect. Severe to profound ID/GDD was observed more for the cases with gain-of-function variants as compared to those with loss-of-function. CACNA1E, CACNA1G, CACNA1F, CACNA2D2 and CACNA1A associated with more severe phenotype. Furthermore, 157 copy number variations (CNVs) spanning calcium genes were identified in DECIPHER database. The leading genes included CACNA1C, CACNA1A, and CACNA1E. Overall, the underlying mechanisms included gain- and/ or loss-of-function, alteration in kinetics (activation, inactivation) and dominant-negative effects of truncated forms of alpha1 subunits. Forty of the identified cases featured cerebellar atrophy. We identified only a few cell and animal studies that focused on the mechanisms of ID/GDD in relation to CCs. There is a scarcity of studies on treatment options for ID/GDD both in vivo and in vitro. Conclusion Our results suggest that CCs play a major role in ID/GDD. While both gain- and loss-of-function variants are associated with ID/GDD, the mechanisms underlying their involvement need further scrutiny.

scholarly journals Case Report: Causative De novo Variants of KCNT2 for Developmental and Epileptic Encephalopathy

2021 ◽  
Vol 12 ◽  
Author(s):  
Pan Gong ◽  
Xianru Jiao ◽  
Dan Yu ◽  
Zhixian Yang
Keyword(s):  
De Novo ◽  
Gene Mutations ◽  
Epileptic Encephalopathy ◽  
Infantile Spasms ◽  
Loss Of Function ◽  
Gain Of Function ◽  
Dysmorphic Features ◽  
Pathogenic Variants ◽  
Ohtahara Syndrome ◽  
Whole Exome

Objective:KCNT2 gene mutations had been described to cause developmental and epileptic encephalopathies (DEEs). In this study, we presented the detailed clinical features and genetic analysis of two unrelated patients carrying two de novo variants in KCNT2 and reviewed eight different cases available in publications.Methods: Likely pathogenic variants were identified by whole exome sequencing; clinical data of the patients were retrospectively collected and analyzed.Results: Our two unrelated patients were diagnosed with Ohtahara syndrome followed by infantile spasms (IS) and possibly the epilepsy of infancy with migrating focal seizures (EIMFS), respectively. They both manifested dysmorphic features with hirsute arms, thick hair, prominent eyebrows, long and thick eyelashes, a broad nasal tip, and short and smooth philtrum. In the eight patients reported previously, two was diagnosed with IS carrying a ‘change-of-function' mutation and a gain-of-function mutation, respectively, two with EIMFS-like carrying a gain-of-function mutation and a loss-of-function mutation, respectively, one with EIMFS carrying a loss-of-function mutation, three with DEE without functional analysis. Among them, two patients with gain-of-function mutations both exhibited dysmorphic features and presented epilepsy phenotype, which was similar to our patients.Conclusion: Overall, the most common phenotypes associated with KCNT2 mutation were IS and EIMFS. Epilepsy phenotype associated with gain- and loss-of-function mutations could overlap. Additional KCNT2 cases will help to make genotype-phenotype correlations clearer.

scholarly journals Functional Characterization of KCNMA1 mutation associated with dyskinesia, seizure, developmental delay, and cerebellar atrophy

2021 ◽  
Author(s):  
Emrah Yucesan ◽  
Beyza Goncu ◽  
Cemil Ozgul ◽  
Arda Kebapci ◽  
Ayca Dilruba Aslanger ◽  
...  
Keyword(s):  
Functional Characterization ◽  
Cerebellar Atrophy ◽  
Bk Channels ◽  
Bk Channel ◽  
Functional Study ◽  
Loss Of Function ◽  
Gain Of Function ◽  
Α Subunit ◽  
Truncating Mutation

Abstract KCNMA1 located on chromosome 10q22.3, encodes the pore-forming α subunit of the “Big K+” (BK) large conductance calcium and voltage-activated K + channel. BK channels are widely distributed across tissues, including both excitable and non excitable cells. Numerous evidence suggests the functional BK channel alterations produced by different KCNMA1 alleles may associate with different symptoms, such as paroxysmal non kinesigenic dyskinesia with gain of function and ataxia with loss of function. Functional classifications revealed two major patterns, gain of function and loss of function effects on channel properties in different cell lines. In the literature, two mutations have been shown to confer gain of function properties to BK channels: D434G and N995S. On the other hand 10 mutations have been classified as loss of function (S351Y,G354S, G356R, G375R, C413Y/N449fs, I663V, P805L, and D984N) or putative loss of function (premature truncation mutations: Y676Lfs*7 and Arg458Ter). In this study, we report the functional characterization of a variant which was previously reported the whole exome sequencing revealed bi-allelic nonsense variation (NM_001161352.1 (ENST00000286628.8):c.1372C > T; Arg458*) of the cytoplasmic domain of calcium-activated potassium channel subunit alpha-1 protein. To detect functional consequences of the variation immunostaining and electrophysiological studies were conducted. In this study, we conducted patch-clamp recordings on WT and R458X mutant cells. We found the gain of function effect for the mutation. This is the first functional study observing an increased current in the KCNMA1 gene resulting from a truncating mutation

scholarly journals Loss-of-Function and Gain-of-Function Mutations in KCNQ5 Cause Intellectual Disability or Epileptic Encephalopathy

2017 ◽  
Vol 101 (1) ◽  
pp. 65-74 ◽  
Author(s):  
Anna Lehman ◽  
Samrat Thouta ◽  
Grazia M.S. Mancini ◽  
Sakkubai Naidu ◽  
Marjon van Slegtenhorst ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Epileptic Encephalopathy ◽  
Loss Of Function ◽  
Gain Of Function

scholarly journals Loss-of-function variants in DNM1 cause a specific form of developmental and epileptic encephalopathy only in biallelic state

2021 ◽  
pp. jmedgenet-2021-107769
Author(s):  
Gökhan Yigit ◽  
Ruth Sheffer ◽  
Muhannad Daana ◽  
Yun Li ◽  
Emrah Kaygusuz ◽  
...  
Keyword(s):  
Neurological Disorders ◽  
Clinical Symptoms ◽  
Epileptic Encephalopathy ◽  
Specific Form ◽  
Loss Of Function ◽  
Epileptic Encephalopathies ◽  
Pathogenic Variants ◽  
Whole Exome ◽  
Heterozygous Carriers ◽  
Refractory Seizures

BackgroundDevelopmental and epileptic encephalopathies (DEEs) represent a group of severe neurological disorders characterised by an onset of refractory seizures during infancy or early childhood accompanied by psychomotor developmental delay or regression. DEEs are genetically heterogeneous with, to date, more than 80 different genetic subtypes including DEE31 caused by heterozygous missense variants in DNM1.MethodsWe performed a detailed clinical characterisation of two unrelated patients with DEE and used whole-exome sequencing to identify causative variants in these individuals. The identified variants were tested for cosegregation in the respective families.ResultsWe excluded pathogenic variants in known, DEE-associated genes. We identified homozygous nonsense variants, c.97C>T; p.(Gln33*) in family 1 and c.850C>T; p.(Gln284*) in family 2, in the DNM1 gene, indicating that biallelic, loss-of-function pathogenic variants in DNM1 cause DEE.ConclusionOur finding that homozygous, loss-of-function variants in DNM1 cause DEE expands the spectrum of pathogenic variants in DNM1. All parents who were heterozygous carriers of the identified loss-of-function variants were healthy and did not show any clinical symptoms, indicating that the type of mutation in DNM1 determines the pattern of inheritance.

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