%0 Journal Article %1 MUKHERJEE2022100131 %A Mukherjee, Souhrid %A Cassini, Thomas A. %A Hu, Ningning %A Yang, Tao %A Li, Bian %A Shen, Wangzhen %A Moth, Christopher W. %A Rinker, David C. %A Sheehan, Jonathan H. %A Cogan, Joy D. %A Newman, John H. %A Hamid, Rizwan %A Macdonald, Robert L. %A Roden, Dan M. %A Meiler, Jens %A Kuenze, Georg %A Phillips, John A. %A Capra, John A. %D 2022 %J Human Genetics and Genomics Advances %K topic_lifescience DEE, Diseases KCNC2, Network, Undiagnosed and biology, developmental disease dynamics electrophysiology, encephalopathy, epileptic interpretation, molecular personalized rare simulations, structural variant variant, %N 4 %P 100131 %R https://doi.org/10.1016/j.xhgg.2022.100131 %T Personalized structural biology reveals the molecular mechanisms underlying heterogeneous epileptic phenotypes caused by de novo KCNC2 variants %U https://www.sciencedirect.com/science/article/pii/S2666247722000471 %V 3 %X Summary Whole-exome sequencing (WES) in the clinic has identified several rare monogenic developmental and epileptic encephalopathies (DEE) caused by ion channel variants. However, WES often fails to provide actionable insight for rare diseases, such as DEEs, due to the challenges of interpreting variants of unknown significance (VUS). Here, we describe a “personalized structural biology” (PSB) approach that leverages recent innovations in the analysis of protein 3D structures to address this challenge. We illustrate this approach in an Undiagnosed Diseases Network (UDN) individual with DEE symptoms and a de novo VUS in KCNC2 (p.V469L), the Kv3.2 voltage-gated potassium channel. A nearby KCNC2 variant (p.V471L) was recently suggested to cause DEE-like phenotypes. Computational structural modeling suggests that both affect protein function. However, despite their proximity, the p.V469L variant is likely to sterically block the channel pore, while the p.V471L variant is likely to stabilize the open state. Biochemical and electrophysiological analyses demonstrate heterogeneous loss-of-function and gain-of-function effects, as well as differential response to 4-aminopyridine treatment. Molecular dynamics simulations illustrate that the pore of the p.V469L variant is more constricted, increasing the energetic barrier for K+ permeation, whereas the p.V471L variant stabilizes the open conformation. Our results implicate variants in KCNC2 as causative for DEE and guide the interpretation of a UDN individual. They further delineate the molecular basis for the heterogeneous clinical phenotypes resulting from two proximal pathogenic variants. This demonstrates how the PSB approach can provide an analytical framework for individualized hypothesis-driven interpretation of protein-coding VUS.

@article{MUKHERJEE2022100131, abstract = {Summary Whole-exome sequencing (WES) in the clinic has identified several rare monogenic developmental and epileptic encephalopathies (DEE) caused by ion channel variants. However, WES often fails to provide actionable insight for rare diseases, such as DEEs, due to the challenges of interpreting variants of unknown significance (VUS). Here, we describe a “personalized structural biology” (PSB) approach that leverages recent innovations in the analysis of protein 3D structures to address this challenge. We illustrate this approach in an Undiagnosed Diseases Network (UDN) individual with DEE symptoms and a de novo VUS in KCNC2 (p.V469L), the Kv3.2 voltage-gated potassium channel. A nearby KCNC2 variant (p.V471L) was recently suggested to cause DEE-like phenotypes. Computational structural modeling suggests that both affect protein function. However, despite their proximity, the p.V469L variant is likely to sterically block the channel pore, while the p.V471L variant is likely to stabilize the open state. Biochemical and electrophysiological analyses demonstrate heterogeneous loss-of-function and gain-of-function effects, as well as differential response to 4-aminopyridine treatment. Molecular dynamics simulations illustrate that the pore of the p.V469L variant is more constricted, increasing the energetic barrier for K+ permeation, whereas the p.V471L variant stabilizes the open conformation. Our results implicate variants in KCNC2 as causative for DEE and guide the interpretation of a UDN individual. They further delineate the molecular basis for the heterogeneous clinical phenotypes resulting from two proximal pathogenic variants. This demonstrates how the PSB approach can provide an analytical framework for individualized hypothesis-driven interpretation of protein-coding VUS.}, added-at = {2024-10-02T10:38:17.000+0200}, author = {Mukherjee, Souhrid and Cassini, Thomas A. and Hu, Ningning and Yang, Tao and Li, Bian and Shen, Wangzhen and Moth, Christopher W. and Rinker, David C. and Sheehan, Jonathan H. and Cogan, Joy D. and Newman, John H. and Hamid, Rizwan and Macdonald, Robert L. and Roden, Dan M. and Meiler, Jens and Kuenze, Georg and Phillips, John A. and Capra, John A.}, biburl = {https://puma.scadsai.uni-leipzig.de/bibtex/298dbf112278a4a1989e9f5120fb695be/scadsfct}, doi = {https://doi.org/10.1016/j.xhgg.2022.100131}, interhash = {18d295a4af426870eaa7f57a36669d95}, intrahash = {98dbf112278a4a1989e9f5120fb695be}, issn = {2666-2477}, journal = {Human Genetics and Genomics Advances}, keywords = {topic_lifescience DEE, Diseases KCNC2, Network, Undiagnosed and biology, developmental disease dynamics electrophysiology, encephalopathy, epileptic interpretation, molecular personalized rare simulations, structural variant variant,}, number = 4, pages = 100131, timestamp = {2024-11-22T15:48:14.000+0100}, title = {Personalized structural biology reveals the molecular mechanisms underlying heterogeneous epileptic phenotypes caused by de novo KCNC2 variants}, url = {https://www.sciencedirect.com/science/article/pii/S2666247722000471}, volume = 3, year = 2022 }