Effect of an autism-associated KCNMB2 variant, G124R, on BK channel properties

Moldenhauer, Hans; Dinsdale, Ria L.; Álvarez, Sara; Fernández-Jaén, A; Meredith, Andrea L.

doi:10.1016/j.crphys.2022.09.001

Cited by 4 publications

(4 citation statements)

References 64 publications

(116 reference statements)

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“…16 However, other top DEGs including CNTNAP4, SLC1A2, and GABRG3 have also been shown to underly irregular firing patterns in the context of epilepsy or autism and could be contributing to the disease mechanism. [69][70][71][72][73][74] It should finally be considered that protein-level interactions could play a larger role as PACS1 has been shown to form a complex with Wdr37 and regulate ER Ca 2+ homeostasis in lymphocytes. 24 Further exploration is needed as the elucidation of the mechanism would be a massive step towards identifying potential therapeutic compounds for PACS1 syndrome patients.…”

Section: Discussionmentioning

confidence: 99%

“…16 However, other top DEGs including CNTNAP4, SLC1A2, and GABRG3 have also been shown to underly irregular firing patterns in the context of epilepsy or autism and could be contributing to the disease mechanism. [69][70][71][72][73][74] It should finally be considered that protein-level interactions could play a larger role as PACS1 has been shown to form a complex with Wdr37 and regulate ER Ca 2+ homeostasis in lymphocytes. 24 Patch clamp recording in combination with pharmacological modulation of candidate ion channels are critical future directions in order to better understand how p.R203W PACS1 impacts action potential dynamics, potentially revealing targets for therapeutic intervention.…”

Section: Discussionmentioning

confidence: 99%

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iPSC-derived models of PACS1 syndrome reveal transcriptional and functional deficits in neuron activity

Rylaarsdam

Guemez‐Gamboa

2022

Preprint

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PACS1 syndrome is a neurodevelopmental disorder characterized by intellectual disability and craniofacial abnormalities resulting from a de novo p.R203W variant in phosphofurin acidic cluster sorting protein 1 (PACS1). PACS1 is known to play roles in both the endosomal pathway and nucleus, but little is known about how this variant affects the developing nervous system and patients have few therapeutic options. Here, we used stem cell-derived forebrain organoids to show that PACS1(+/R203W) cells share convergent molecular features of autism spectrum disorder (ASD) through a gain-of-function mechanism. These features include an aberrant propensity towards GABAergic differentiation, increased inhibitory synaptic density, and impaired expression of an ASD-specific gene network enriched at synapses. This work is the first to investigate the impact of the p.R203W variant on the developing brain and suggests a therapy that either clears p.R203W PACS1 or targets convergent pathological mechanisms of ASD could be beneficial for patients.

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Section: Discussionmentioning

confidence: 99%

“…16 However, other top DEGs including CNTNAP4, SLC1A2, and GABRG3 have also been shown to underly irregular firing patterns in the context of epilepsy or autism and could be contributing to the disease mechanism. [69][70][71][72][73][74] It should finally be considered that protein-level interactions could play a larger role as PACS1 has been shown to form a complex with Wdr37 and regulate ER Ca 2+ homeostasis in lymphocytes. 24 Patch clamp recording in combination with pharmacological modulation of candidate ion channels are critical future directions in order to better understand how p.R203W PACS1 impacts action potential dynamics, potentially revealing targets for therapeutic intervention.…”

Section: Discussionmentioning

confidence: 99%

iPSC-derived models of PACS1 syndrome reveal transcriptional and functional deficits in neuron activity

Rylaarsdam

Guemez‐Gamboa

2022

Preprint

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“…YFP fluorescence was used to identify transfected cells. These tags do not affect BK current properties under these conditions (25,26) and have been used in our previous studies (11,25,(27)(28)(29). Deactivation kinetics were measured by fitting the tail current decay with a single exponential function in pCLAMP 10.6 (Molecular Devices, San Jose, CA, USA).…”

Section: Synthesis Of Kcnma1 Patient Variants In the Human Bk Channelmentioning

confidence: 99%

Section: Synthesis Of Kcnma1 Patient Variants In the Human Bk Channelmentioning

confidence: 99%

Structural mapping of patient-associatedKCNMA1gene variants

Moldenhauer,

Tammen,

Meredith

2023

Preprint

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KCNMA1 linked channelopathy is a neurological disorder produced by malfunctioning of the BK channel, characterized by seizure, motor abnormalities, and neurodevelopmental disability. Twenty-one KCNMA1 patient-associated variants have been classified as gain-of-function (GOF) or loss of function (LOF) in BK channel activity, and the remaining ~40% are variants of uncertain significance (VUS). To address the physical relationships, this study analyzed KCNMA1 missense variants within the context of BK channel cryoEM structures. Clusters of LOF variants were identified in the pore, within the AC region (RCK1), and near the Ca2+ bowl (RCK2), overlapping with sites of pharmacological or endogenous modulation. However, no clustering relationship was found for GOF variants. Next, variants were analyzed with widely used pathogenicity algorithms. The individual performances of REVEL, Mutpred, MetaLR, and CADD/PHRED were compared for each variant, incorporating them into a weighted summation model (WSM). The WSM component was integrated with BK channel structural parameters in a modular algorithm to generate a 'KCNMA1 meta score' (KMS). KMS performance showed a 7% difference from the highest performing individual algorithm (REVEL). Several functionally uncharacterized variants that showed different predictions between KMS and REVEL were assessed further using electrophysiological recordings of BK currents. Two KMS positive; REVEL negative variants were confirmed pathogenic (M578T and D965V), and one KMS negative; REVEL positive variant was confirmed non pathogenic (D800Y). However, KMS failed to accurately categorize two variants (E656A and K457E). Thus, although incorporation of structural data within the KMS algorithm results in a small performance improvement, its predictive capabilities will be increased as more disease delineated variants are functionally tested, new structural components are available, and novel functional modules are developed.

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