Voltage-gated K+ (Kv) channels are tetrameric complexes of proteins encoded by KCN genes. Gain-of-function (GoF) mutations in KCNH1 (Kv10.1, hEAG1) and KCNH5 (Kv10.2, hEAG2) give rise to developmental disorders, intellectual disability, and epilepsy. Currently, clinical symptoms are not straightforwardly associated with functional properties of mutated channels. Here we investigated how members of the KCNH subfamily are affected by heteromerization with mutant Kv10.1 or Kv10.2 protein subunits. The de novo variant Kv10.1-G496E, which leads to impaired neurodevelopment and epilepsy, was expressed alone or with other wild-type subunits in HEK293T cells and characterized using whole-cell patch clamp. While Kv10.1-G496E alone did not yield functional K+ channels, coexpression with Kv10.1 or Kv10.2 shifted the half-maximum voltage of activation in the hyperpolarizing direction. Likewise, the homologous mutation Kv10.2-G465E did not yield functional channels but also induced GoF upon coexpression with wild-type Kv10.1 or Kv10.2. By contrast, the mutants did not affect the function of Kv11.1 (KCNH2, hERG1) channels. To infer the relevance of Kv10 GoF mutations under physiological conditions, we used the fluorescent genetically encoded voltage indicator mK2-rEstus and found that both, Kv10.1 and Kv10.2, hyperpolarized HEK293T cells, and that coexpression of the GoF mutants augmented this hyperpolarization. Our findings imply that interpretation of clinical symptoms related to Kv10 GoF mutations requires considering the functional crosstalk with Kv10.1 and Kv10.2 subunits, which are both expressed in glutamatergic neurons in cortical Layers III and IV.

Epilepsy is a common but heterogeneous neurological disorder characterized by recurrent seizures resulting from aberrant hypersynchronous electrical discharges in all or part of the brain. While there are numerous potential causes, such as traumatic brain injury, stroke and infection, many epilepsies have a genetic basis. Here we review the molecular basis, clinical phenotype and treatment options for KCNH1 epilepsy, which is caused by gain-of-function mutations in the gene KCNH1, encoding the voltage-gated potassium channel Kv10.1. Although first discovered in patients with Temple-Baraitser syndrome and Zimmermann-Laband syndrome, these genetic disorders are now recognized as belonging to a broad spectrum of KCNH1-related encephalopathies characterized by developmental delay, intellectual disability, facial dysmorphism and infantile-onset seizures. A major challenge in developing disease-specific anti-seizure medications for KCNH1 epilepsy is selectivity over Kv11.1 (hERG), a closely related channel that plays a fundamental role in repolarization of the cardiac action potential and which is uniquely susceptible to inhibition by a diverse range of drugs. We argue that allosteric modulators of Kv10.1 that induce a depolarizing shift in the channel's activation threshold are more likely to provide seizure control in KCNH1 epilepsy patients than pore blockers that annihilate channel function.

Small conductance Ca2+-activated K+ channels (SK channels) are widely expressed in the central nervous system, where they play a crucial role in modulating neuronal excitability. Recent studies have identified missense variants in the genes encoding SK2 and SK3 channels as the cause of two rare neurodevelopmental disorders: NEDMAB and ZLS3, respectively. Here, we used Caenorhabditis elegans as an in vivo model to investigate the functional consequences of these patient variants. The C. elegans orthologue KCNL-1 regulates neuronal and muscle excitability in the egg-laying system, a well-characterized model circuit. To visualize KCNL-1 expression and localization, we generated a fluorescent translational reporter at the endogenous kcnl-1 locus. We then introduced eight point mutations corresponding to pathogenic variants reported in NEDMAB or ZLS3 patients. Our study confirmed the molecular pathogenicity of the ZLS3-associated mutations, revealing a gain-of-function effect that led to increased in utero egg retention, likely due to electrical silencing of the egg-laying circuitry. NEDMAB mutations exhibited more complex phenotypic effects. Most caused a loss-of-function phenotype, indistinguishable from null mutants, while one displayed a clear gain-of-function effect. Additionally, a subset of NEDMAB variants altered KCNL-1 localization, suggesting an impairment in channel biosynthesis, trafficking or stability. These findings provide new insights into the molecular mechanisms underlying NEDMAB and ZLS3 physiopathology, enhancing our understanding of SK channel dysfunction in human disease. Moreover, they establish C. elegans as a robust and cost-effective in vivo model for rapid functional validation of new SK channel mutations, paving the way for future investigations.

Hereditary gingival fibromatosis (HGF) is a rare condition characterised by the abnormal growth of gingival tissue, leading to a thickened and fibrous appearance of the gingiva. It can show syndromic and non-syndromic associations. In this case report, the surgical management of HGF associated with the Zimmermann-Laband syndrome was successfully carried out using three different methods: conventional gingivectomy, electrocautery and diode laser gingivectomy. These techniques have proven to be effective in treating hereditary gingival fibromatosis, restoring normal gingival appearance and improving overall oral health.

The KCNH1 gene (OMIM #603,305) encodes a voltage-gated potassium channel primarily found in the central nervous system. Recent discoveries have linked pathogenic variations in this gene to Temple-Baraitser syndrome (TMBTS, OMIM #611,816) and Zimmermann-Laband syndrome (ZLS, OMIM #135,500). A common manifestation of these syndromes is gingival fibromatosis, which may partially or completely cover tooth crowns, leading in some cases to functional and aesthetic problems, as well as delayed tooth eruption. A four-year-old boy and his parents first consulted for delayed primary molars eruption. Shortly after birth, he was diagnosed with a developmental encephalopathy caused by a de novo pathogenic variant in KCNH1. The first step of oral treatment consisted of myofunctional and speech/language therapy to stimulate biting and chewing. It also helped with the rehabilitation of proper tongue function. This was followed by a gingivoplasty to expose the submerged teeth. We propose a clinical approach to optimize disease management. This aims to minimize complications associated with this rare disorder. This case illustrates the need for appropriate and early gingivoplasty to prevent teeth impaction and restore dental function. Additionally, it explores potential complications and provides grounds for a comprehensive protocol for managing gingival fibromatosis for patients with KCNH1 variant.