Houdayer Clara, Phillips A Marie, Chabbert Marie, Bourreau Jennifer, Maroofian Reza, Houlden Henry, Richards Kay, Saadi Nebal Waill, Dad'ová Eliška, Van Bogaert Patrick, Rupin Mailys, Keren Boris, Charles Perrine, Smol Thomas, Riquet Audrey, Pais Lynn, O'Donnell-Luria Anne, VanNoy Grace E, Bayat Allan, Møller Rikke S, Olofsson Kern, Jamra Rami Abou, Syrbe Steffen, Dasouki Majed, Seaver Laurie H, Sullivan Jennifer A, Shashi Vandana, Alkuraya Fowzan S, Poss Alexis F, Spence J Edward, Schnur Rhonda E, Forster Ian C, Mckenzie Chaseley E, Simons Cas, Wang Min, Snell Penny, Kothur Kavitha, Buckley Michael, Roscioli Tony, Elserafy Noha, Dauriat Benjamin, Procaccio Vincent, Henrion Daniel, Lenaers Guy, Colin Estelle, Verbeek Nienke E, Van Gassen Koen L, Legendre Claire, Bonneau Dominique, Reid Christopher A, Howell Katherine B, Ziegler Alban, Legros Christian
Department of Medical Genetics, Angers University Hospital, Angers, France.
Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Victoria, Australia.
Ann Neurol. 2025 Jun 5. doi: 10.1002/ana.27277.
We aimed to characterize the phenotypic spectrum and functional consequences associated with variants in HCN2, encoding for the hyperpolarization-activated cyclic nucleotide (HCN) gated channel 2.
GeneMatcher facilitated the recruitment of 21 individuals with HCN2 variants from 15 unrelated families, carrying HCN2 variants. In vitro functional studies were performed by electrophysiology with Xenopus laevis oocytes and membrane trafficking was investigated in HEK cells by confocal imaging. Structural 3D-analysis of the HCN2 variants was performed.
The phenotypic spectrum included developmental delay/intellectual disability (DD/ID, 17/21), epilepsy (10/21), language disorders (16/21), movement disorders (12/21), and axial hypotonia (10/21). Thirteen pathogenic variants (12 new and 1 already described) were identified: 11 missense (8 monoallelic and 3 biallelic), 1 recurrent inframe deletion (monoallelic), and 1 frameshift (biallelic). Functional analysis of p.(Arg324His) variant showed a strong increase of HCN2 conductance, whereas p.(Ala363Val) and p.(Met374Leu) exhibited dominant negative effects. The p.(Leu377His), p.(Pro493Leu), and p.(Gly587Asp) variants rendered HCN2 electrophysiologically silent and impaired membrane trafficking. Structural 3D-analysis revealed that, except for p.(Arg324His), all variants altered HCN2 stability.
Our findings broadened the HCN2 disease clinical spectrum to include DD/ID with or without epilepsy. Functional analysis in cellular models reveal that pathogenic HCN2 variants can cause either loss-of-function or gain-of-function, providing critical information for the development of targeted therapies for HCN2-related disorders. ANN NEUROL 2025.
我们旨在描述与超极化激活环核苷酸（HCN）门控通道2编码基因HCN2变异相关的表型谱和功能后果。
通过基因匹配平台，从15个无关家庭招募了21名携带HCN2变异的个体。利用非洲爪蟾卵母细胞进行电生理体外功能研究，并通过共聚焦成像在人胚肾（HEK）细胞中研究膜转运。对HCN2变异进行三维结构分析。
表型谱包括发育迟缓/智力残疾（DD/ID，17/21）、癫痫（10/21）、语言障碍（16/21）、运动障碍（12/21）和轴性肌张力减退（10/21）。鉴定出13个致病变异（12个新变异和1个已报道变异）：11个错义变异（8个单等位基因和3个双等位基因）、1个复发性框内缺失变异（单等位基因）和1个移码变异（双等位基因）。对p.(Arg324His)变异的功能分析显示HCN2电导显著增加，而p.(Ala363Val)和p.(Met374Leu)表现出显性负效应。p.(Leu377His)、p.(Pro493Leu)和p.(Gly587Asp)变异使HCN2在电生理上无活性，并损害膜转运。三维结构分析表明，除p.(Arg324His)外，所有变异均改变了HCN2的稳定性。
我们的研究结果拓宽了HCN2疾病的临床谱，包括伴或不伴癫痫的DD/ID。细胞模型中的功能分析表明，致病性HCN2变异可导致功能丧失或功能获得，为开发针对HCN2相关疾病的靶向治疗提供了关键信息。《神经病学纪事》2025年。
