Mutant Channels Research Articles

Pro-arrhythmic effects of gain-of-function potassium channel mutations in the short QT syndrome.

The congenital short QT syndrome (SQTS) is a rare condition characterized by abbreviated rate-corrected QT (QTc) intervals on the electrocardiogram and by increased susceptibility to both atrial and ventricular arrhythmias and sudden death. Although mutations to multiple genes have been implicated in the SQTS, evidence of causality is particularly strong for the first three (SQT1-3) variants: these result from gain-of-function mutations in genes that encode K+ channel subunits responsible, respectively, for the IKr, IKs and IK1 cardiac potassium currents. This article reviews evidence for the impact of SQT1-3 missense potassium channel gene mutations on the electrophysiological properties of IKr, IKs and IK1 and of the links between these changes and arrhythmia susceptibility. Data from experimental and simulation studies and future directions for research in this field are considered. This article is part of the theme issue 'The heartbeat: its molecular basis and physiological mechanisms'.

Channelopathies in Epilepsy: from Precision Medicine to Gene Therapy

Epilepsy is a common and debilitating neurological disease with a significant genetic component. Inherited or de novo mutations in ion channels resulting in periodic network hyperexcitability is a major cause of epileptogenesis. Understanding of the genetic etiology of epilepsy opens up the avenue of personalized treatment. A range of precision medications are designed to target the defective ion channels, with varied effects. In addition, the underlying mechanisms of channelopathies can also be addressed by gene therapy. Expression of mutated ion channel genes can be regulated via gene replacement or gene silencing approaches, including viral vector-mediated gene replacement and antisense oligonucleotides. Aside from directly compensating of ion channel dysfunction, another strategy of gene therapy involves the overexpression of certain ion channels to modulate neuronal excitability, which particularly targets focal epilepsies. In line with the paroxysmal nature of epileptic seizures, optogenetic and chemogenetic approaches, which permits conditional activation of gene products can be particularly beneficial. The ideal gene therapy to treat genetic epilepsies and channelopathies would be in vivo gene editing, making precise gene modifications to correct mutations harbored by each individual. Advances in CRISPR- Cas technology has brought the idea closer to reality, yet technical and ethical concerns surround its therapeutic application.

Regulation of the two-pore domain potassium channel, THIK-1 and THIK-2, by G protein coupled receptors.

A member of THIK (two pore domain halothane-inhibited K+) channels, THIK-1, was reported as a target of Gi/o-coupled receptors (Gi/o-Rs) in neurons and microglia. We confirmed that in HEK293T cells the THIK-1 channel is activated by Gi/o-Rs and found that Gq-coupled receptors (Gq-Rs) also activates the channel. The effects of Gi/o-Rs and Gq-Rs were inhibited by the Gi/o inhibitor pertussis toxin and phospholipase C (PLC) inhibitor, respectively. The effects of Gi/o-Rs were attenuated when consensus Gβγ binding motif at the C-tail of the THIK-1 channel was mutated, suggesting that Gβγ serves as a THIK-1 channel activator upon the stimulation of Gi/o-Rs. As to the effects of Gq-Rs on the THIK-1 channel, a protein kinase C inhibitor and calcium chelators failed to inhibit the effect of a Gq coupled muscarinic M1R. Neither the hydrolysis of phosphatidyl inositol bisphosphate induced by voltage sensitive phosphatase nor the application of a diacylglycerol analogue, OAG, increased the channel current. The mediator of Gq-dependent activation of the THIK-1 channel remained unsolved. The effects of Gi/o- and Gq-Rs on the THIK-2 channel were also investigated, by using a THIK-2 mutant channel whose N-terminal domain is deleted to improve the surface membrane expression. We observed that Gi/o- and Gq-Rs activate the mutated THIK-2 channel, similarly to the THIK-1 channel. Interestingly, heterodimeric channels of THIK-1 and THIK-2 responded to Gi/o-R and Gq-R stimulation. Taken together, Gi/o- or Gq-Rs activates the THIK-1 and THIK-2 channels in a Gβγ or PLC dependent manner, respectively.

PRAX-562 is a Well-Tolerated, Novel Persistent Sodium Channel Blocker with Broad Anticonvulsant Activity in Multiple DEE Mouse Models (S34.007)

PRAX-562 is a Well-Tolerated, Novel Persistent Sodium Channel Blocker with Broad Anticonvulsant Activity in Multiple DEE Mouse Models (S34.007)

Lymphatic contractile dysfunction in mouse models of Cantú Syndrome with KATP channel gain-of-function.

Cantú Syndrome (CS) is an autosomal dominant disorder caused by gain-of-function (GoF) mutations in the Kir6.1 and SUR2 subunits of KATP channels. KATP overactivity results in a chronic reduction in arterial tone and hypotension, leading to other systemic cardiovascular complications. However, the underlying mechanism of lymphedema, developed by>50% of CS patients, is unknown. We investigated whether lymphatic contractile dysfunction occurs in mice expressing CS mutations in Kir6.1 (Kir6.1[V65M]) or SUR2 (SUR2[A478V], SUR2[R1154Q]). Pressure myograph tests of contractile function of popliteal lymphatic vessels over the physiological pressure range revealed significantly impaired contractile strength and reduced frequency of spontaneous contractions at all pressures in heterozygous Kir6.1[V65M] vessels, compared to control littermates. Contractile dysfunction of intact popliteal lymphatics in vivo was confirmed using near-infrared fluorescence microscopy. Homozygous SUR2[A478V] vessels exhibited profound contractile dysfunction ex vivo, but heterozygous SUR2[A478V] vessels showed essentially normal contractile function. However, further investigation of vessels from all three GoF mouse strains revealed significant disruption in contraction wave entrainment, decreased conduction speed and distance, multiple pacemaker sites, and reversing wave direction. Tests of 2-valve lymphatic vessels forced to pump against an adverse pressure gradient revealed that all CS-associated genotypes were essentially incapable of pumping under an imposed outflow load. Our results show that varying degrees of lymphatic contractile dysfunction occur in proportion to the degree of molecular GoF in Kir6.1 or SUR2. This is the first example of lymphatic contractile dysfunction caused by a smooth muscle ion channel mutation and potentially explains the susceptibility of CS patients to lymphedema.

Electrophysiological characterization of a CaV3.1 calcium channel mutation linked to trigeminal neuralgia.

Trigeminal neuralgia is a rare and debilitating disorder that affects one or more branches of the trigeminal nerve, leading to severe pain attacks and a poor quality of life. It has been reported that the CaV3.1 T-type calcium channel may play an important role in trigeminal pain and a recent study identified a new missense mutation in the CACNA1G gene that encodes the pore forming α1 subunit of the CaV3.1 calcium channel. The mutation leads to a substitution of an Arginine (R) by a Glutamine (Q) at position 706 in the I-II linker region of the channel. Here, we used whole-cell voltage-clamp recordings to evaluate the biophysical properties of CaV3.1 wild-type and R706Q mutant channels expressed in tsA-201 cells. Our data indicate an increase in current density in the R706Q mutant, leading to a gain-of-function effect, without changes in the voltage for half activation. Moreover, voltage clamp using an action potential waveform protocol revealed an increase in the tail current at the repolarization phase in the R706Q mutant. No changes were observed in the voltage-dependence of inactivation. However, the R706Q mutant displayed a faster recovery from inactivation. Hence, the gain-of-function effects in the R706Q CaV3.1 mutant have the propensity to impact pain transmission in the trigeminal system, consistent with a contribution to trigeminal neuralgia pathophysiology.

Protocolo diagnóstico de las parálisis periódicas

Current molecular technology has shown that there are mutations in multiple voltage-dependent ion channels. The most frequent mutations are those which affect sodium channels (hyperkalaemic periodic paralysis, paramyotonia congenita, potassium-aggravated myotonia, etc.), potassium channels (Andersen-Tawil syndrome) and the chlorine channel (congenital myotonia). Even so much work still remains to be done to characterize the symptoms and physiopathology even more thoroughly and thereby establish more effective treatments.

Dietary Supplementation with Milk Lipids Leads to Suppression of Developmental and Behavioral Phenotypes of Hyperexcitable Drosophila Mutants

Dietary modifications often have a profound impact on the penetrance and expressivity of neurological phenotypes that are caused by genetic defects. Our previous studies in Drosophila melanogaster revealed that seizure-like phenotypes of gain-of-function voltage-gated sodium (Nav) channel mutants (paraShu, parabss1, and paraGEFS+), as well as other seizure-prone “bang-sensitive” mutants (eas and sda), were drastically suppressed by supplementation of a standard diet with milk whey. In the current study we sought to determine which components of milk whey are responsible for the diet-dependent suppression of their hyperexcitable phenotypes. Our systematic analysis reveals that supplementing the diet with a modest amount of milk lipids (0.26% w/v) mimics the effects of milk whey. We further found that a minor milk lipid component, α-linolenic acid, contributed to the diet-dependent suppression of adult paraShu phenotypes. Given that lipid supplementation during the larval stages effectively suppressed adult paraShu phenotypes, dietary lipids likely modify neural development to compensate for the defects caused by the mutations. Consistent with this notion, lipid feeding fully rescued abnormal dendrite development of class IV sensory neurons in paraShu larvae. Overall, our findings demonstrate that milk lipids are sufficient to ameliorate hyperexcitable phenotypes in Drosophila mutants, providing a foundation for future investigation of the molecular and cellular mechanisms by which dietary lipids modify genetically induced abnormalities in neural development, physiology, and behavior.

BK channels of five different subunit combinations underlie the de novo KCNMA1 G375R channelopathy.

The molecular basis of a severe developmental and neurological disorder associated with a de novo G375R variant of the tetrameric BK channel is unknown. Here, we address this question by recording from single BK channels expressed to mimic a G375R mutation heterozygous with a WT allele. Five different types of functional BK channels were expressed: 3% were consistent with WT, 12% with homotetrameric mutant, and 85% with three different types of hybrid (heterotetrameric) channels assembled from both mutant and WT subunits. All channel types except WT showed a marked gain-of-function in voltage activation and a smaller decrease-of-function in single-channel conductance, with both changes in function becoming more pronounced as the number of mutant subunits per tetrameric channel increased. The net cellular response from the five different types of channels comprising the molecular phenotype was a shift of -120 mV in the voltage required to activate half of the maximal current through BK channels, giving a net gain-of-function. The WT and homotetrameric mutant channels in the molecular phenotype were consistent with genetic codominance as each displayed properties of a channel arising from only one of the two alleles. The three types of hybrid channels in the molecular phenotype were consistent with partial dominance as their properties were intermediate between those of mutant and WT channels. A model in which BK channels randomly assemble from mutant and WT subunits, with each subunit contributing increments of activation and conductance, approximated the molecular phenotype of the heterozygous G375R mutation.

Nav1.7 gain-of-function mutation I228M triggers age-dependent nociceptive insensitivity and C-LTMR dysregulation

Gain-of-function mutations in Scn9a, which encodes the peripheral sensory neuron-enriched voltage-gated sodium channel Nav1.7, cause paroxysmal extreme pain disorder (PEPD), inherited erythromelalgia (IEM), and small fiber neuropathy (SFN). Conversely, loss-of-function mutations in the gene are linked to congenital insensitivity to pain (CIP). These mutations are evidence for a link between altered sodium conductance and neuronal excitability leading to somatosensory aberrations, pain, or its loss. Our previous work in young adult mice with the Nav1.7 gain-of-function mutation, I228M, showed the expected DRG neuron hyperexcitability, but unexpectedly the mice had normal mechanical and thermal behavioral sensitivity. We now show that with aging both male and female mice with this mutation unexpectedly develop a profound insensitivity to noxious heat and cold, as well skin lesions that span the body. Electrophysiology demonstrates that, in contrast to young mice, aged I228M mouse DRGs have a profound loss of sodium conductance and changes in activation and slow inactivation dynamics, representing a loss-of-function. Through RNA sequencing we explored how these age-related changes may produce the phenotypic changes and found a striking and specific decrease in C-low threshold mechanoreceptor- (cLTMR) associated gene expression, suggesting a potential contribution of this DRG neuron subtype to Nav1.7 dysfunction phenotypes. A GOF mutation in a voltage-gated channel can therefore produce over a prolonged time, highly complex and unexpected alterations in the nervous system beyond excitability changes.

KATP channel mutations in congenital hyperinsulinism: Progress and challenges towards mechanism-based therapies.

Congenital hyperinsulinism (CHI) is the most common cause of persistent hypoglycemia in infancy/childhood and is a serious condition associated with severe recurrent attacks of hypoglycemia due to dysregulated insulin secretion. Timely diagnosis and effective treatment are crucial to prevent severe hypoglycemia that may lead to life-long neurological complications. In pancreatic β-cells, adenosine triphosphate (ATP)-sensitive K+ (KATP) channels are a central regulator of insulin secretion vital for glucose homeostasis. Genetic defects that lead to loss of expression or function of KATP channels are the most common cause of HI (KATP-HI). Much progress has been made in our understanding of the molecular genetics and pathophysiology of KATP-HI in the past decades; however, treatment remains challenging, in particular for patients with diffuse disease who do not respond to the KATP channel activator diazoxide. In this review, we discuss current approaches and limitations on the diagnosis and treatment of KATP-HI, and offer perspectives on alternative therapeutic strategies.

Diacylglycerol Activates the Drosophila Light Sensitive Channel TRPL Expressed in HEK Cells.

Physiological activation by light of the Drosophila TRP and TRP-like (TRPL) channels requires the activation of phospholipase Cβ (PLC). The hydrolysis of phosphatidylinositol 4,5, bisphosphate (PIP2) by PLC is a crucial step in the still-unclear light activation, while the generation of Diacylglycerol (DAG) by PLC seems to be involved. In this study, we re-examined the ability of a DAG analogue 1-oleoyl-2-acetyl-sn-glycerol (OAG) to activate the TRPL channels expressed in HEK cells. Unlike previous studies, we added OAG into the cytosol via a patch-clamp pipette and observed robust activation of the expressed TRPL channels. However, TRPL channel activation was much slower than the physiologically activated TRPL by light. Therefore, we used a picosecond-fast optically activated DAG analogue, OptoDArG. Inactive OptoDArG was added into the intracellular solution with the patch-clamp pipette, and it slowly accumulated on the surface membrane of the recorded HEK cell in the dark. A fast application of intense UV light to the recorded cell resulted in a robust and relatively fast TRPL-dependent current that was greatly accelerated by the constitutively active TRPLF557I pore-region mutation. However, this current of the mutant channel was still considerably slower than the native light-induced TRPL current, suggesting that DAG alone is not sufficient for TRPL channel activation under physiological conditions.

An Improved Feedforward-Robust Algorithm for Active Vibration Control of Helicopter Maneuver Flight

To solve the problem of secondary path mutation and external disturbance abrupt changes during helicopter maneuver flight, the previous research proposed a hybrid active vibration control law. To improve the engineering applicability, the original algorithm is ameliorated to the least mean square-input-output-based robust (LMS-IOBR) algorithm. The system model within the target frequency band can be identified through the input-output data to avoid constructing complex state observers. In addition, the output form of the feedback controller is constructed by an autoregressive moving average model with extra input, which is beneficial to improve operational efficiency. Numerical simulations demonstrate that compared with the original algorithm, controller real-time computation can be reduced by 52% with control effects guaranteed at the same time. Furthermore, to verify the effectiveness and adaptability of LMS-IOBR, multi-input multioutput vibration control experiments are carried out on a specially developed simple platform for simulating helicopter maneuver states. Comparative tests in various typical states are performed between the LMS-IOBR and the multichannel least mean square algorithm. Under the complex circumstances of simulating continuous subduction uplift, the peak response of closed-loop system attenuates by 80% and 70%, and the vibration of two points is reduced to 15% and 20%, respectively, within 3 s. The experimental results demonstrate that the proposed LMS-IOBR algorithm shows stronger transient adaptability and robustness against external disturbance excitation and secondary channel mutation in helicopter maneuver flight.

The Effect of TWIK-1 Two Pore Potassium Channels on Cardiomyocytes in Low Extracellular Potassium Conditions.

At low extracellular potassium ([K+]e) conditions, human cardiomyocytes can depolarize to -40 mV. This is closely related to hypokalemia-induced fatal cardiac arrhythmia. The underlying mechanism, however, is still not well understood. TWIK-1 channels are background K+ channels that are highly expressed in human cardiomyocytes. We previously reported that TWIK-1 channels changed ion selectivity and conducted leak Na+ currents at low [K+]e. Moreover, a specific threonine residue (Thr118) within the ion selectivity filter was responsible for this altered ion selectivity. Patch clamp were used to investigate the effects of TWIK-1 channels on the membrane potentials of cardiomyocytes in response to low [K+]e. At 2.7 mM [K+]e and 1 mM [K+]e, both Chinese hamster ovary (CHO) cells and HL-1 cells ectopically expressed human TWIK-1 channels displayed inward leak Na+ currents and reconstitute depolarization of membrane potential. In contrast, cells ectopically expressed human TWIK-1-T118I mutant channels that remain high selectivity to K+ exhibited hyperpolarization of membrane potential. Furthermore, human iPSC-derived cardiomyocytes showed depolarization of membrane potential in response to 1 mM [K+]e, while the knockdown of TWIK-1 expression eliminated this phenomenon. These results demonstrate that leak Na+ currents conducted by TWIK-1 channels contribute to the depolarization of membrane potential induced by low [K+]e in human cardiomyocytes.

Ion channels in neurodevelopment: lessons from the Integrin-KCNB1 channel complex.

Ion channels modulate cellular excitability by regulating ionic fluxes across biological membranes. Pathogenic mutations in ion channel genes give rise to epileptic disorders that are among the most frequent neurological diseases affecting millions of individuals worldwide. Epilepsies are triggered by an imbalance between excitatory and inhibitory conductances. However, pathogenic mutations in the same allele can give rise to loss-of-function and/or gain-of-function variants, all able to trigger epilepsy. Furthermore, certain alleles are associated with brain malformations even in the absence of a clear electrical phenotype. This body of evidence argues that the underlying epileptogenic mechanisms of ion channels are more diverse than originally thought. Studies focusing on ion channels in prenatal cortical development have shed light on this apparent paradox. The picture that emerges is that ion channels play crucial roles in landmark neurodevelopmental processes, including neuronal migration, neurite outgrowth, and synapse formation. Thus, pathogenic channel mutants can not only cause epileptic disorders by altering excitability, but further, by inducing morphological and synaptic abnormalities that are initiated during neocortex formation and may persist into the adult brain.

A sleep-active neuron can promote survival while sleep behavior is disturbed.

Sleep is controlled by neurons that induce behavioral quiescence and physiological restoration. It is not known, however, how sleep neurons link sleep behavior and survival. In Caenorhabditis elegans, the sleep-active RIS neuron induces sleep behavior and is required for survival of starvation and wounding. Sleep-active neurons such as RIS might hypothetically promote survival primarily by causing sleep behavior and associated conservation of energy. Alternatively, RIS might provide a survival benefit that does not depend on behavioral sleep. To probe these hypotheses, we tested how activity of the sleep-active RIS neuron in Caenorhabditis elegans controls sleep behavior and survival during larval starvation. To manipulate the activity of RIS, we expressed constitutively active potassium channel (twk-18gf and egl-23gf) or sodium channel (unc-58gf) mutant alleles in this neuron. Low levels of unc-58gf expression in RIS increased RIS calcium transients and sleep. High levels of unc-58gf expression in RIS elevated baseline calcium activity and inhibited calcium activation transients, thus locking RIS activity at a high but constant level. This manipulation caused a nearly complete loss of sleep behavior but increased survival. Long-term optogenetic activation also caused constantly elevated RIS activity and a small trend towards increased survival. Disturbing sleep by lethal blue-light stimulation also overactivated RIS, which again increased survival. FLP-11 neuropeptides were important for both, induction of sleep behavior and starvation survival, suggesting that FLP-11 might have divergent roles downstream of RIS. These results indicate that promotion of sleep behavior and survival are separable functions of RIS. These two functions may normally be coupled but can be uncoupled during conditions of strong RIS activation or when sleep behavior is impaired. Through this uncoupling, RIS can provide survival benefits under conditions when behavioral sleep is disturbed. Promoting survival in the face of impaired sleep might be a general function of sleep neurons.

Transfluthrin enhances odorant receptor-mediated spatial repellency in Aedes aegypti

Mosquito-borne diseases are an increasing global health challenge and vector-based interventions remain the most important methods for reducing the public health burden of most mosquito-borne diseases. Transfluthrin, a volatile pyrethroid insecticide, is used widely and effectively as an insecticide and as a repellent. In a recent study, we showed that at very low concentrations transfluthrin repels Aedes aegypti mosquitoes in a hand-in-cage assay without detectable stimulation of antennal olfactory responses. Furthermore, activation of sodium channels by transfluthrin enhances repellency by DEET, which has been reported to repel mosquitoes via odorant receptor (Or)-dependent and Or-independent mechanisms. However, whether activation of sodium channels by transfluthrin can serve as a general mechanism for synergizing the activities of other repellents remain unknown. In this study, we found that, in hand-in-cage assay, transfluthrin enhanced repellency by geranyl acetate and (E)-β-farnesene, which activate AaOr31. Such enhancement was not observed in AaOr31-knockout mosquitoes and dampened in a pyrethroid-resistant strain carrying two sodium channel mutations, which reduce the action of transfluthrin on sodium channels. In addition, transfluthrin also enhanced repellency by (−)-borneol, (±)-citronellal, camphor, and eucalyptol, which activate Or-mediated repellency. Our study has uncovered the ability of transfluthrin to enhance the repellency to a variety of mosquito repellents, beyond DEET, and provided experimental support for the emerging paradigm of synergistic interactions between repellency mediated by sodium channel activation and Or activation. These findings have potential implications in the development of more effective mosquito repellent mixtures.

Contrasting Patterns of Asaia Association with Pyrethroid Resistance Escalation between the Malaria Vectors Anopheles funestus and Anopheles gambiae

Microbiome composition has been associated with insecticide resistance in malaria vectors. However, the contribution of major symbionts to the increasingly reported resistance escalation remains unclear. This study explores the possible association of a specific endosymbiont, Asaia spp., with elevated levels of pyrethroid resistance driven by cytochrome P450s enzymes and voltage-gated sodium channel mutations in Anopheles funestus and Anopheles gambiae. Molecular assays were used to detect the symbiont and resistance markers (CYP6P9a/b, 6.5 kb, L1014F, and N1575Y). Overall, genotyping of key mutations revealed an association with the resistance phenotype. The prevalence of Asaia spp. in the FUMOZ_X_FANG strain was associated with the resistance phenotype at a 5X dose of deltamethrin (OR = 25.7; p = 0.002). Mosquitoes with the resistant allele for the markers tested were significantly more infected with Asaia compared to those possessing the susceptible allele. Furthermore, the abundance correlated with the resistance phenotype at 1X concentration of deltamethrin (p = 0.02, Mann-Whitney test). However, for the MANGOUM_X_KISUMU strain, findings rather revealed an association between Asaia load and the susceptible phenotype (p = 0.04, Mann-Whitney test), demonstrating a negative link between the symbiont and permethrin resistance. These bacteria should be further investigated to establish its interactions with other resistance mechanisms and cross-resistance with other insecticide classes.

Binding of RPR260243 at the intracellular side of the hERG1 channel pore domain slows closure of the helix bundle crossing gate.

The opening and closing of voltage-dependent potassium channels is dependent on a tight coupling between movement of the voltage sensing S4 segments and the activation gate. A specific interaction between intracellular amino- and carboxyl-termini is required for the characteristically slow rate of channel closure (deactivation) of hERG1 channels. Compounds that increase hERG1 channel currents represent a novel approach for prevention of arrhythmia associated with prolonged ventricular repolarization. RPR260243 (RPR), a quinoline oxo-propyl piperidine derivative, inhibits inactivation and dramatically slows the rate of hERG1 channel deactivation. Here we report that similar to its effect on wild-type channels, RPR greatly slows the deactivation rate of hERG1 channels missing their amino-termini, or of split channels lacking a covalent link between the voltage sensor domain and the pore domain. By contrast, RPR did not slow deactivation of C-terminal truncated hERG1 channels or D540K hERG1 mutant channels activated by hyperpolarization. Together, these findings indicate that ability of RPR to slow deactivation requires an intact C-terminus, does not slow deactivation by stabilizing an interaction involving the amino-terminus or require a covalent link between the voltage sensor and pore domains. All-atom molecular dynamics simulations using the cryo-EM structure of the hERG1 channel revealed that RPR binds to a pocket located at the intracellular ends of helices S5 and S6 of a single subunit. The slowing of channel deactivation by RPR may be mediated by disruption of normal S5-S6 interactions.

A novel gain of function mutation in TPC2 reiterates pH-pigmentation interplay: Emerging role of ionic homeostasis as a master pigmentation regulator

Pigmentation is a complex physiological phenomenon that protects from UV induced damage. Perturbations in pigmentation pathways lead to pigmentary disorders such as vitiligo, albinism and Darier...s disease. Emerging literature implicates a critical role of ionic homeostasis and pH in regulating pigmentation. In a recent study, Wang et al. identified a novel gain of function mutation in a non-selective cation channel “Two Pore Channel 2” (TPC2) that is responsible for albinism in a human patient. The authors demonstrate that this mutation leads to constitutive activation of TPC2 thereby modulating cellular calcium dynamics and inducing changes in the lysosomal pH. Further, authors generated a knock in mice with homologous TPC2 mutation and corroborated a causative role for this mutation in albinism. It is an exciting study that reports a novel TPC2 mutation, which is responsible for albinism in an autosomal dominant inheritance fashion. Since TPC2 is localized on melanosomes as well, going forward it would be interesting to investigate the role of this mutation on melanosomal calcium dynamics and alterations in melanosomal pH.