Two CaV3.3 (CACNA1I) Gain-of-Function Mutations Linked to Epilepsy and Intellectual Disability Affect Gating Properties and the Window Current

Loss-of-function mutations in the KV4.3 channel-encoding KCND3 gene are linked to neurodegenerative cerebellar ataxia. Patients suffering from neurodegeneration associated with iron deposition may also present with cerebellar ataxia. The mechanism underlying brain iron accumulation remains unclear. Here, we aim to ascertain the potential pathogenic role of KCND3 variant in iron accumulation-related cerebellar ataxia. We presented a patient with slowly progressive cerebellar ataxia, parkinsonism, cognitive impairment, and iron accumulation in the basal ganglia and the cerebellum. Whole exome sequencing analyses identified in the patient a heterozygous KCND3 c.1256G>A (p.R419H) variant predicted to be disease-causing by multiple bioinformatic analyses. In vitro biochemical and immunofluorescence examinations revealed that, compared to the human KV4.3 wild-type channel, the p.R419H variant exhibited normal protein abundance and subcellular localization pattern. Electrophysiological investigation, however, demonstrated that the KV4.3 p.R419H variant was associated with a dominant increase in potassium current amplitudes, as well as notable changes in voltage-dependent gating properties leading to enhanced potassium window current. These observations indicate that, in direct contrast with the loss-of-function KCND3 mutations previously reported in cerebellar ataxia patients, we identified a rare gain-of-function KCND3 variant that may expand the clinical and molecular spectra of neurodegenerative cerebellar disorders associated with brain iron accumulation.

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ABCC9-related Intellectual disability Myopathy Syndrome is a KATP channelopathy with loss-of-function mutations in ABCC9

Nature Communications ◽

10.1038/s41467-019-12428-7 ◽

2019 ◽

Vol 10 (1) ◽

Cited By ~ 5

Author(s):

Marie F. Smeland ◽

Conor McClenaghan ◽

Helen I. Roessler ◽

Sanne Savelberg ◽

Geir Åsmund Myge Hansen ◽

...

Keyword(s):

Intellectual Disability ◽

Cardiac Dysfunction ◽

Systolic Dysfunction ◽

Splice Site Mutation ◽

Cerebral White Matter ◽

Sulfonylurea Receptor ◽

Loss Of Function ◽

Mild Intellectual Disability ◽

Site Mutation ◽

Gain Of Function

Abstract Mutations in genes encoding KATP channel subunits have been reported for pancreatic disorders and Cantú syndrome. Here, we report a syndrome in six patients from two families with a consistent phenotype of mild intellectual disability, similar facies, myopathy, and cerebral white matter hyperintensities, with cardiac systolic dysfunction present in the two oldest patients. Patients are homozygous for a splice-site mutation in ABCC9 (c.1320 + 1 G > A), which encodes the sulfonylurea receptor 2 (SUR2) subunit of KATP channels. This mutation results in an in-frame deletion of exon 8, which results in non-functional KATP channels in recombinant assays. SUR2 loss-of-function causes fatigability and cardiac dysfunction in mice, and reduced activity, cardiac dysfunction and ventricular enlargement in zebrafish. We term this channelopathy resulting from loss-of-function of SUR2-containing KATP channels ABCC9-related Intellectual disability Myopathy Syndrome (AIMS). The phenotype differs from Cantú syndrome, which is caused by gain-of-function ABCC9 mutations, reflecting the opposing consequences of KATP loss- versus gain-of-function.

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Gain-of-Function Mutations inRARBCause Intellectual Disability with Progressive Motor Impairment

Human Mutation ◽

10.1002/humu.23004 ◽

2016 ◽

Vol 37 (8) ◽

pp. 786-793 ◽

Cited By ~ 20

Author(s):

Myriam Srour ◽

Véronique Caron ◽

Toni Pearson ◽

Sarah B. Nielsen ◽

Sébastien Lévesque ◽

...

Keyword(s):

Intellectual Disability ◽

Motor Impairment ◽

Gain Of Function

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Homozygous STXBP1 variant causes encephalopathy and gain-of-function in synaptic transmission

Brain ◽

10.1093/brain/awz391 ◽

2019 ◽

Vol 143 (2) ◽

pp. 441-451 ◽

Cited By ~ 7

Author(s):

Hanna C A Lammertse ◽

Annemiek A van Berkel ◽

Michele Iacomino ◽

Ruud F Toonen ◽

Pasquale Striano ◽

...

Keyword(s):

Intellectual Disability ◽

Synaptic Transmission ◽

Protein Stability ◽

Developmental Delay ◽

Fold Increase ◽

Null Mouse ◽

Gain Of Function ◽

Gene Encoding ◽

Cellular Effects ◽

Protein Levels

Abstract Heterozygous mutations in the STXBP1 gene encoding the presynaptic protein MUNC18-1 cause STXBP1 encephalopathy, characterized by developmental delay, intellectual disability and epilepsy. Impaired mutant protein stability leading to reduced synaptic transmission is considered the main underlying pathogenetic mechanism. Here, we report the first two cases carrying a homozygous STXBP1 mutation, where their heterozygous siblings and mother are asymptomatic. Both cases were diagnosed with Lennox-Gastaut syndrome. In Munc18-1 null mouse neurons, protein stability of the disease variant (L446F) is less dramatically affected than previously observed for heterozygous disease mutants. Neurons expressing Munc18L446F showed minor changes in morphology and synapse density. However, patch clamp recordings demonstrated that L446F causes a 2-fold increase in evoked synaptic transmission. Conversely, paired pulse plasticity was reduced and recovery after stimulus trains also. Spontaneous release frequency and amplitude, the readily releasable vesicle pool and the kinetics of short-term plasticity were all normal. Hence, the homozygous L446F mutation causes a gain-of-function phenotype regarding release probability and synaptic transmission while having less impact on protein levels than previously reported (heterozygous) mutations. These data show that STXBP1 mutations produce divergent cellular effects, resulting in different clinical features, while sharing the overarching encephalopathic phenotype (developmental delay, intellectual disability and epilepsy).

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Calcium channelopathies and intellectual disability: a systematic review

Orphanet Journal of Rare Diseases ◽

10.1186/s13023-021-01850-0 ◽

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.

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Autism with Seizures and Intellectual Disability: Possible Causative Role of Gain-of-function of the Inwardly-Rectifying K+ Channel Kir4.1

Neurobiology of Disease ◽

10.1016/j.nbd.2011.03.016 ◽

2011 ◽

Vol 43 (1) ◽

pp. 239-247 ◽

Cited By ~ 72

Author(s):

Federico Sicca ◽

Paola Imbrici ◽

Maria Cristina D'Adamo ◽

Francesca Moro ◽

Fabrizia Bonatti ◽

...

Keyword(s):

Intellectual Disability ◽

K Channel ◽

Causative Role ◽

Gain Of Function ◽

Inwardly Rectifying

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Intellectual disability-associated gain-of-function mutations in CERT1 that encodes the ceramide transport protein CERT

PLoS ONE ◽

10.1371/journal.pone.0243980 ◽

2020 ◽

Vol 15 (12) ◽

pp. e0243980

Author(s):

Hiroaki Murakami ◽

Norito Tamura ◽

Yumi Enomoto ◽

Kentaro Shimasaki ◽

Kenji Kurosawa ◽

...

Keyword(s):

Intellectual Disability ◽

Biochemical Analysis ◽

Developmental Disorder ◽

Adaptive Functioning ◽

Transport Protein ◽

Evidence Based ◽

Sequencing Analysis ◽

Gain Of Function ◽

Whole Exome ◽

Organelle Trafficking

Intellectual disability (ID) is a developmental disorder that includes both intellectual and adaptive functioning deficits in conceptual, social, and practical domains. Although evidence-based interventions for patients have long been desired, their progress has been hindered due to various determinants. One of these determinants is the complexity of the origins of ID. The ceramide transport protein (CERT) encoded by CERT1 mediates inter-organelle trafficking of ceramide for the synthesis of intracellular sphingomyelin. Utilizing whole exome sequencing analysis, we identified a novel CERT variant, which substitutes a serine at position 135 (S135) for a proline in a patient with severe ID. Biochemical analysis showed that S135 is essential for hyperphosphorylation of a serine-repeat motif of CERT, which is required for down-regulation of CERT activity. Amino acid replacements of S135 abnormally activated CERT and induced an intracellular punctate distribution pattern of this protein. These results identified specific ID-associated CERT1 mutations that induced gain-of-function effects on CERT activity. These findings provide a possible molecular basis for not only new diagnostics but also a conceivable pharmaceutical intervention for ID disorders caused by gain-of-function mutations in CERT1.

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