HCN2-Associated Neurodevelopmental Disorders: Data from Patients and Xenopus Cell Models.

Area of Science:

• Neurogenetics
• Molecular Neuroscience
• Channelopathies

Background:

• The hyperpolarization-activated cyclic nucleotide (HCN) gated channel 2 (HCN2) plays a critical role in neuronal excitability.
• Dysfunction of HCN2 is implicated in various neurological disorders, but its full phenotypic spectrum and molecular mechanisms remain incompletely understood.

Purpose of the Study:

• To comprehensively characterize the phenotypic spectrum and functional consequences of variants in the HCN2 gene.
• To elucidate the molecular mechanisms underlying HCN2-related channelopathies.

Main Methods:

• Recruitment of 21 individuals from 15 families with HCN2 variants using GeneMatcher.
• In vitro functional studies including electrophysiology in Xenopus laevis oocytes and membrane trafficking analysis in HEK cells.
• Structural 3D-analysis of identified HCN2 variants.

Main Results:

• Identified a broad phenotypic spectrum including developmental delay/intellectual disability (DD/ID), epilepsy, language disorders, movement disorders, and axial hypotonia.
• Characterized 13 pathogenic HCN2 variants (12 novel), including missense, inframe deletion, and frameshift types.
• Demonstrated diverse functional consequences: gain-of-function (e.g., p.Arg324His), dominant-negative effects (e.g., p.Ala363Val, p.Met374Leu), and loss-of-function with impaired trafficking (e.g., p.Leu377His, p.Pro493Leu, p.Gly587Asp).

Conclusions:

• Expanded the clinical spectrum of HCN2-related disorders to encompass DD/ID with or without epilepsy.
• Established that pathogenic HCN2 variants can lead to either loss-of-function or gain-of-function mechanisms.
• Provided critical insights for the development of targeted therapeutic strategies for HCN2 channelopathies.