Acknowledgments

Introduction

In the broadest sense, channelopathies can be defined as diseases associated with malfunction of ion channels or their regulatory proteins. Although this definition covers both congenital and acquired forms, generally only hereditary diseases are referred to as channelopathies in which disease mutations in genes encoding ion channel subunits or regulatory proteins play an etiological role [1]. In hereditary transient receptor potential (TRP) channelopathies, a TRP channel is affected by the mutation. Recently, several hereditary TRP channelopathies have been described, and they have been discussed in many comprehensive reviews [2–5]. The increasing number of TRP channel-related diseases highlights these channels as novel pharmaceutical targets and also provide insight into its physiological function [6]. In this review, we describe hereditary channelopathies and also mention examples with available genetic evidence to explain several putative pathological conditions in which TRP dysfunction is suggested, although the primary mutations affect other genes. We refer also for in-depth information the OMIM link channelopathies.

TRPC Channelopathies

TRP channels are linked to diseases since their first description. The discovery of the founding member of the TRP superfamily, the Drosophila TRP channel, was already due to a drosophila channelopathy disrupting the phototransduction and resulting in blindness of the fruit fly [7]. The closest mammalian relatives of the Drosophila TRP, members of the canonical (TRPC) subfamily, have been linked to many acquired diseases affecting, among else, cardiovascular and respiratory systems, skin, inflammatory processes, and probably neurodegenerative diseases [8], but there are only few examples for “real” hereditary TRPC channelopathies. In this review, we will not refer to hereditary diseases linked to store-operated (STIM/ORAI/TRPCs “?”) Ca^2 + channels, although evidence has been reported for their involvement in several disease (e.g., severe combined immune deficiency [9], primary Sjogren’s syndrome [10], and tubular-aggregate myopathy [11]).

TRPC1 can play a role in several skin diseases [12], including a few hereditary ones. Recently, it was discussed to be involved in the Gorlin (or Gorlin-Goltz) syndrome, a rare basal cell nevus syndrome with autosomal dominant hereditary (OMIM 109400). The syndrome has 100% penetrance and variable expressivity characterized by odontogenic keratocysts of the mandible, postnatal tumors, and multiple basal cell carcinomas (BCCs). Although it is mostly linked to mutations in the tumor suppressor gene PTCH1, a member of the patched gene family and receptor for sonic hedgehog, in some cases the TRPC1 gene was suggested to be involved in the development of many postnatal tumors [13]. Indeed, the lack of TRPC1 (and TRPC4) was also correlated with failure of differentiation in BCC cells [14]. The autosomal-dominant inherited skin malady, Darier(-White) disease (DD) or keratosis follicularis, characterized by hyperkeratotic papules, might also be connected to TRPC1 malfunction, although the primary causes are mutations in the atp2a2 gene encoding the SERCA2b endoplasmic reticulum Ca^2 + pump [15]. In DD patients’ keratinocytes, increased protein expression and TRPC1-mediated Ca^2 + influx were detected, which can contribute to the augmented proliferation and survival of DD keratinocytes [16]. Beyond the skin, TRPC1 can be associated with other hereditary diseases. For example, a novel spliced isoform of TRPC1 with exon 9 deletion (TRPC1E9del) was reported in a human ovarian adenocarcinoma cell line, and its role (together with other TRPC isoforms) in the proliferation and differentiation is also discussed [17]. In a genome-wide association study, SNPs in TRPC1 were discovered that were associated with type 2 diabetes [18]. The role of TRPC1 and ORAI1 might also be implicated in several angiogenesis syndromes leading to tumor neovascularization, which are frequently due to mutations in the Von Hippel Lindau tumor suppressor gene [19].

TRPC3 is mostly linked to the central nervous system by hereditary diseases. In mice, a gain-of-function mutation in TRPC3 (T635A) caused degeneration of cerebellar Purkinje cells and a loss of type II unipolar brush cells, resulting in a cerebellar ataxia, the moonwalker mouse phenotype [20,21]. A single base pair polymorphism (rs13121031) located within the CpG island in the alternative promoter of the human TRPC3 gene was also connected to cerebellar ataxia and heart hypertrophy [22]. Although the link between TRPC3 and cerebellar ataxia is fairly strong in the aforementioned mouse models, there has not been any evidence presented in humans. However, a genetic screen for TRPC3 mutations in patients with late-onset cerebellar ataxia does not support a contribution of TRPC3 mutants to this disease [23]. TRPC3 might be indirectly targeted in various inherited diseases affecting the nervous system. One of them is the autosomal-dominant Spinocerebellar ataxia type 14 (SCA14) primary caused by mutations in PKCγ. Wild-type PKCγ negatively regulated TRPC3 channels, whose regulation was impaired in cerebellar Purkinje cells transfected with the S119P mutant isoform resulting in increased postsynaptic current amplitudes. This alteration could contribute to disruptive synapse pruning disturbing synaptic transmission and plasticity found in SCA14 patients [24]. TRPC3 might also be involved in another neurodevelopmental disorder, the Williams-Beuren syndrome, which is associated with hypercalcemia and heart or blood vessel problems. The main genetic defect generally lays in the transcription factor IIi gene that encodes TFII-I, which normally suppresses cell-surface accumulation of TRPC3, i.e., mutations in TFII-I can cause a TRPC3 gain-of-function due to increased protein expression in the plasma membrane [25]. The pervasive developmental disorder Rett syndrome (RTT), affecting mostly female patients and causing mental retardation, is a progressive neurodevelopmental disorder that can also be linked to TRPC3. RTT is caused by mutations in the gene MECP2 (methyl CpG binding protein 2) encoding a transcriptional regulator protein with mostly repressive functions [26]. TRPC3 has been identified recently as target of MeCP2 transcriptional regulation, and it was suggested to be involved in the impaired brain-derived neurotrophic factor signaling in RTT [27]. An SNP in TRPC3 (rs6820068) was also found to be associated with the risk to develop immunoglobulin A-induced nephropathy (IgA nephropathy, IgAN) in women; the prevalence of the SNP was 23% vs. 12% in female patients and healthy controls, respectively [28]. Some pharmacological evidence proposed that excessive Ca^2 + influx via TRPC3 contributed to Ca^2 + toxicity in pancreas and salivary gland, whose symptoms are characteristic for acute pancreatitis and Sjögren syndrome, a systemic autoimmune disease, in which immune cells destroy exocrine cells in tear glands, pancreas, and salivary glands [29].

TRPC4 has not been directly connected to any channelopathy yet. However, a genetic association study has shown some link between TRPC4 SNPs and generalized photosensitive epilepsies and related symptoms [30]. Furthermore, a missense SNP caused gain-of-function mutation in TRPC4 (I957V) that was suggested to be protective against myocardial infarction [31].

TRPC6, with other TRPC channels, was linked to infantile hypertrophic pyloric stenosis (IHPS) (OMIM 179010), the most common gastrointestinal obstruction disease in infancy with genetic background affecting the smooth muscle of the pylorus. A linkage analysis in IHPS identified SNPs in two genetic loci involving TRPC5 and TRPC6 [32] and later also SNPs affecting TRPC1. An SNP in the promoter region and a missense variant in exon 4 of TRPC6 are hypothesized as putative causal gene variants [33]. However, another study carried out on Chinese patients and healthy controls has not found association between IHPS and other SNPs in TRPC6 [34].

TRPC6 plays an important role in glomerular diseases in the kidney. Among them, several cases of focal and segmental glomerulosclerosis (FSGS type 2) (OMIM 603965) are considered as a real TRPC6 channelopathies; currently, at least 15 mutations in the N- and C-terminus of the TRPC6 gene have been described and linked to FSGS type 2 (for review, see Ref. [35], new mutations in Refs. [36,37]). FSGS is functionally characterized by proteinuria and progressive decline of renal function caused by malfunction or loss of podocytes. Podocytes are highly specialized epithelial cells lining the Bowman’s capsule and playing a key role in the function of the glomerular filtration barrier. Although it is not fully understood, yet, how mutations in TRPC6 lead to dysfunction or death of podocytes impairing glomerular permeability and filtration and finally resulting in FSGS, the investigation of the mutants’ phenotypes highlighted two most probably interdependent mechanisms: altered channel functions and impaired interactions with other proteins. The distorted protein-protein interaction can consequently alter regulation and/or trafficking of the channel, significantly influencing channel properties or expression. In podocytes, TRPC6 associates with the transmembrane protein nephrin, which is coupled to the nephrin-interacting adapter protein, CD2AP, and to podocin. This complex forms the slit diaphragm, the crucial component of the glomerular filter. Nephrin is known to negatively regulate the expression of TRPC6 in the plasma membrane ([38], for a review, see Ref. [39]). By the mechanism, nephrin was shown to inhibit TRPC6-PLC-γ1 interaction, which seems to be crucial in the membrane trafficking of the channel. Some of the described mutations (e.g., P112Q, N143S, S270T, R885C, E897K) may affect the nephrin binding site of the TRPC6, making it less sensitive for the nephrin-dependent negative regulation, which results in higher surface expression and enhanced TRPC6-mediated Ca^2 + entry [40]. Although it is a fact that most of the TRPC6 mutations described in FSGS are associated with a gain-of-function phenotype and TRPC6-mediated calcium entry was found to mediate both angiotensine-II and albumin overload-induced loss of podocytes [41,42], downstream mechanisms, i.e., how overactivation of TRPC6 destroys the slit, are still under discussion. A very likely mechanism is the activation of nuclear factor of activated T-cells (NFAT) found in TRPC6 mutants. This effect was blocked by inhibitors of calcineurin, calmodulin-dependent kinase II, and phosphatidylinositol 3-kinase, but was found to be independent of Src, Yes, or Fyn ([43,44]; see for a review, Ref. [45]). Moreover, angiotensin II-induced Ca^2 + entry via TRPC6 further increased the expression of the channel via calcineurin-NFAT signaling forming a positive feedback loop [41]. Recently, the Wnt/β-catenin and the MAP kinase ERK1/ 2-associated signaling pathways have also been suggested to be involved in the pathogenesis of TRPC6-mediated diabetic podocyte injury [46,47]. Interestingly, vitamin D downregulated the enhanced TRPC6 expression in podocytes through a direct effect on TRPC6 promoter activity, which might contribute to the antiproteinuric effect of vitamin D [48]. It has to be mentioned that the effect of TRPC6 overactivation can be context dependent: for example, acute activation of TRPC6, at least in mice, rescues podocytes from complement-mediated damage; however, chronic overactivation seems to play an etiological role in FSGS [49]. TRPC6 is also involved in the steroid-resistant nephrotic syndrome (SRNS) (OMIM 600995). Three mutations and an intronic nucleotide substitution were described in the sporadic form of this disease [50]. An additional SNP in the promoter region of TRPC6 was also described, which resulted in enhanced transcription in vitro and correlated with an increased protein expression in the kidney of SRNS patients [51]. Mutations in TRPC6 may also contribute to the idiopathic pulmonary arterial hypertension, where an SNP in the promoter region was found more frequently in a cohort of patients. This mutation facilitated the binding of the inflammatory and carcinogenic transcription factor nuclear factor-κB and resulted in abnormally enhanced TRPC6 transcription [52]. TRPC6 is also mentioned as a candidate gene for Head and Neck Squamous Cell Carcinoma [53], and its overexpression in leukocytes was also demonstrated in primary open-angle glaucoma [54].

TRPV Channelopathies

Transient receptor potential vanilloid 1 (TRPV1) the best characterized TRP channel, is not yet clearly linked to any hereditary disease. Although its central integrator role in nociception is widely accepted, only a few polymorphisms in TRPV1 are suggested associating with development and maintenance of chronic pain syndromes. Genetic variants of human TRPV1 with M315I mutation were found more frequently in Caucasian females suffering from neuropathic pain [55], and an intronic variant SNP (rs222741) in TRPV1 was found to be associated with migraine in a Spanish population [56]. Interestingly, the aforementioned M315I variation also showed higher frequency in type 1 diabetes-affected patients than in healthy controls in an Ashkenazi Jewish population [57]. In a patient with Miller-Dieker lissencephaly syndrome, an autosomal-dominant congenital disorder characterized by a developmental defect of the brain as a consequence of incomplete neuronal migration, a chromosome 17p13.3 deletion syndrome was identified, which includes, among else, deletion of TRPV1 [58]. A missense (I585V) variant of TRPV1 gene, showing decreased channel activity, was reported to be a potential genetic risk factor of painful knee osteoarthritis [59], and the same substitution also associated with lower risk of the symptoms of active asthma [60]. Another genetic TRPV1 variant (G315C) was linked to a functional dyspepsia in a Japanese population via influencing the upper gastrointestinal sensation [61].

Altered channel function and/or expression of TRPV2 has been widely connected to Duchenne muscular myopathy, diabetes, childhood asthma, and several forms of cancer [3,62–64]. Currently, elevated expression of TRPV2 has been described in induced pluripotent stem cell-derived endothelial cells (iPSC-ECs) of patients affected by Hutchinson-Gillford progeria syndrome (HGPS; OMIM 176670), a rare genetic disorder in which the premature aging in multiple organs leads to early death. Elevated TRPV2 expression might be involved in the pathomechanism: it caused a sustained [Ca^2 +]_i elevation in HGPS iPSC-ECs induced by hypotonicity, which induced apoptosis. However, despite its potential role in several diseases, no “real” hereditary TRPV2 channelopathy has been detected so far.

TRPV3 is one of the most abundantly expressed TRP channels in epidermal and follicular keratinocytes of both human and rodent skin (for recent reviews, see Refs. [12,65,66]). Olmsted syndrome (OS) (also known as mutilating palmoplantar keratoderma with periorificial keratotic plaques or Polykeratosis of Touraine), (OMIM 614594) is the first described hereditary cutaneous TRP channelopathy and also the first real TRPV3 channelopathy. It is a rare inheritable skin disease characterized by the combination of periorificial, keratotic plaques, bilateral palmoplantar keratodermas, alopecia and associated with dermatosis and severe itching. In humans, three gain-of-function mutations (G573S, G573C, W692G) were identified causing OS (for recent reviews, see Refs. [65–68]). Recently, a new TRPV3 mutant, G573A, has been described in an OS patient, which also causes multiple immune dysfunctions, such as hyper-IgE, elevated follicular T-cells, and persistent eosinophilia [69]. These findings turn the attention toward the immunological alterations of Olmsted syndrome and the potential role of TRPV3 mutants in the immunological dysregulation. The etiological role of TRPV3 mutants is also supported by rodent models DS-Nh mice and WBN/Kob-Ht rats, where two gain-of-function mutations, partly identical with the above ones found in OS, caused autosomal-dominant hairless phenotype associated with dermatitis [70]. Moreover, the hair growth regulatory role of TRPV3 was also evidenced in human [71]. Further supporting the role of TRPV3 as an important channel in skin pathophysiology, an upregulation of TRPV3 was reported in Rosacea, a frequent chronic inflammatory skin disease [72]. Recent studies have suggested that the pathophysiological role of TRPV3 can go beyond skin disorders. Genetic association studies have highlighted a potential role of the channel in primary headache disorders (like migraine, tension-type headache, and cluster headache) with a genetic preposition [73]. TRPV3 SNPs has also been identified in congenital hyperinsulinism of infancy [74].

The TRPV4 coding sequence is a real hot spot of mutations causing channelopathies. Currently, more than 50 mutations in the trpv4 gene have been discovered, causing at least nine different channelopathies. By their symptoms, TRPV4 channelopathies cover skeletal dysplasias and peripheral neuropathies, although mixed forms are also well known, and a clear distinction between these two groups of TRPV4 channelopathies is not always possible. The first recognized TRPV4-related channelopathy, the brachyolmia type 3 (OMIM 113500), affects the skeletal system. It is a relatively mild, autosomal-dominant skeletal dysplasia characterized by short stature, flattened vertebrae (platysspondyly) especially in the cervical region, reduced intervertebral spaces, and scoliosis or kyphosis [75]. This surprising finding triggered intensive research focusing on the newly recognized relationship between TRPV4 and skeletal disorders and resulted in the discovery of new TRPV4 channelopathies among skeletal dysplasias. These diseases share the main symptoms like short stature, platysspondyly, defects in bone ossification, and abnormalities in joints, but their severity shows a high variation not only among the different diseases but also among the different mutations underlying the same symptoms. Despite the variability in the symptoms’ severity, all diseases are probably due to dysfunction and differentiation abnormalities in chondrocytes of the bone growth plate. In the spondyloepimetaphyseal dysplasia Maroteaux pseudo-Morquio type 2 (SEDM-PM2) (OMIM 184095), the manifestations of the preceding symptoms are limited to the musculoskeletal system [76]. In the spondylometaphyseal dysplasia Kozlowski type (OMIM 184252), mainly the vertebrae and the metaphyses are affected. Although, like in the previous cases, the body length is normal at birth, it shows short stature by shortening of the trunk during the development, which reaches the clinical significance mostly between ages 1 and 4 years. Generally, the symptoms are more severe than in brachyolmia type 3 and SEDM-PM2: a prominent feature is platyspondyly again, but severe scoliosis and defects in the distal metaphysis of the femur, the femoral neck, and trochanteric area are also observed. [77]. The most severe skeletal TRPV4 channelopathy is the metatropic dysplasia (OMIM 156530), which is sometimes combined with lethal fetal akinesia. The nonlethal forms are characterized by shortening of all long bones resulting in short limbs, serious enlargement of joints, heavy kyphoscoliosis, severe platyspondyly, and metaphyseal enlargement, as well as defects in ossification [77–79]. Parastremmic dysplasia (PD) (OMIM 168400) is characterized by severe dwarfism, thoracic kyphosis, and distortion and twisting of the limbs [parastremmic (Greek): twisted], contractures of the large joints, malformations of the vertebrae and pelvis, and it can also associate with incontinence [76]. A recently described mild form of skeletal dysplasia is the familial digital arthropathy-brachydactyly (OMIM 606835) which appears in the first decade of life. Short fingers, deviations in finger joints, and irregularities in the articular surfaces characterize this arthropathy [80].

Following the description of an increasing number of TRPV4-caused skeletal dysplasias, the discovery of the causal role of TRPV4 in inherited neuropathies was a big surprise. As of today, three autosomal-dominant distal neuropathies are considered as hereditary TRPV4 channelopathies. Their main symptom is muscle atrophy caused by degeneration of the motoneurons in the spinal ventral horn, leading to muscle weakness and wasting in the distal limbs, but the respiratory system and the vocal cord can be also affected, and sometimes the motor symptoms are associated with sensory defects (for a review, see Ref. [81]). These diseases are congenital distal spinal muscle atrophy (CDSMA) (OMIM 600175), scapuloperoneal spinal muscle atrophy (SPSMA) (OMIM 181405), and hereditary motor sensory neuropathy type IIc (HMSN IIc or Charcot-Marie-Tooth neuropathy type 2C, CMT2C) (OMIM 606071). CDSMA is a nonprogressive lower motor neuron disorder restricted to the lower part of the body. It may associate with arthrogryposis (now also discovered in patients with mutations in the gene encoding the mechanosensory cation channel PIEZO2 [82]), bilateral talipes equinovarus, and flexion contractures of the knees and hips. Sometimes slight skeletal symptoms (e.g., lordosis, scoliosis, restricted joint movements) are also observed, but sensory defects are lacking [83]. SPSMA is a syndrome characterized by scapuloperoneal atrophy, scapular winging, muscle wasting in the lower limbs, absence of tendon reflexes, as well as laryngeal palsy and vocal-cord paralysis. Sometimes scoliosis and light sensory defects are reported [84–86]. In CMTC2C, a variable degree of muscle weakness of limbs, vocal cords, intercostal muscles, and sensoneurial hearing loss are the leading symptoms, but bladder urgency or incontinency are also common. It is often associated with slight skeletal or arthrial symptoms like club foot (talipes), congenital joint contractures (arthrogryposis), or scoliosis, but facial asymmetry, tongue fasciculations, and third and sixth cranial nerve palsies have also been reported. CMTC2 starts in infancy or childhood, and the life expectancy is shortened because of respiratory failure [85–88]. The exact pathomechanism by which mutations in TRPV4 are leading to the aforementioned diseases is vaguely understood, as are the reasons for the phenotype variability of TRPV4 channelopathies (i.e., why diverse mutations result in these different diseases) [89]. Although there are some exceptions and controversies, most of the disease-causing mutations show a gain-of-function phenotype, and there are speculations that the degree of channel overactivity might determine the severity of the disease ([90,91]; for reviews, see Refs. [89,92,93]). The increased, or at least altered, Ca^2 + signaling via TRPV4 can result in altered neurogenesis, altered gene expression, or even cell death. On the other hand, mutations can affect the association of TRPV4 subunits with each other or other molecules influencing channel formation, interaction with cytoskeletal elements, cellular trafficking, or spatial distribution; the latter can have a significant effect on the differentiation of polarized cells like osteocytes or neurons. Indeed, if we have a look at the distribution of the mutations along the amino acid sequence of the channel, three hot spots can be identified for disease-causing mutations: (1) the ankyrin-repeat-domain (ARD) on the N-terminus, (2) the transmembrane region S3-S5, and (3) a C-terminal region were the channel associates with several members of the cytoskeleton, such as tubulin, actin, and MAP7 [94]. Regarding the ARD, the neuropathy-causing mutations are mainly localized in the convex surface of the ARD, but mutations causing skeletal dysplasia, although scattering through the whole length of the channel protein, seem to be more frequently located in the concave surface of the ARD. Because of our limited knowledge, the puzzle created by the large number of mutations often located in the same domain of the channel and the consequent (at least) nine different diseases is still challenging [89]. To make the picture of TRPV4 channelopathies even more complex, we have to mention that TRPV4 is highly expressed in the inner ear and the urothelium; therefore, it is not surprising that some patients also have hearing problems or bladder symptoms such as overactive bladder and incontinence (for a review, see Ref. [95]).

Beyond the aforementioned real channelopathies, a recently recognized human TRPV4 variant (P19S) was linked to acquired chronic obstructive pulmonary disease (COPD). The presence of this mutant probably predisposes the carriers to COPD as a consequence of air pollution (e.g., diesel exhaust particles) because of a reduced airway clearance due to decreased cilia activity, which is supposed to be a TRPV4-dependent mechanism [96]. The same mutation/polymorphism can also cause hyponatremia [97].

TRPV5 and TRPV6, the two close relatives showing the highest Ca^2 + selectivity in the TRP superfamily, function as Ca^2 + (re)absorption channels in the kidney. Although none of the known human channelopathies has been affecting any of them yet, nonsynonymous SNPs in TRPV5 gene show high frequency among African Americans. Among the investigated mutations, A563T variant (and, with lower efficacy, also L712F) was found to increase Ca^2 + permeability of TRPV5 resulting in increased Ca^2 + reabsorption. This mechanism can contribute to increased Ca^2 + retention found in the African-American population [98]. Both TRPV5 and TRPV6 can be involved in the pathomechanism of Pendred syndrome, a form of congenital deafness. The primary cause of the disease is a malfunction of the Cl⁻/HCO3− exchanger, SLC26A4 (pendrin), which results in acidification of the endolymph of the inner ear. Because both TRPV5 and TRPV6 are sensitive to acidification, their inhibition by low pH leads to disturbances in the Ca^2 + concentration of the endolymph [99]. Another carrier disease is Geitelman´s syndrome, which is characterized by salt-losing hypotension, hypomagnesemia, and hypokalemic metabolic alkalosis due to mutations in the thiazide-sensitive Na⁺/Cl⁻ cotransporter gene SLC12A3 and can also indirectly involve the malfunction of TRPV5 and TRPV6 [100]. Although no human equivalent exists so far, in HCALC1 mice model, an autosomal-dominant hypercalciuria can be considered as a real hereditary TRPV5 channelopathy caused by S682P mutation [101]. Their importance in the overall Ca^2 + homeostasis is also supported by the fact that upregulation of both channels causes hypocalciuria [100]. However, rather controversially, an ancestral TRPV6 haplotype consisting three missense mutations by nonsynonymous polymorphisms showed a gain-of-function phenotype and seemed to increase the risk for calcium stone formation in certain forms of absorptive hypercalciuria [102,103].

TRPM Channelopathies

Transient receptor potential melastatin 1 (TRPM1) was previously considered a tumor suppressor protein in melanoma cells, where the name of the whole melastatin subfamily stems from. Although the loss of TRPM1 channel protein is an excellent marker of melanoma aggressiveness, recently miRNA211 coded in an intron of TRPM1 was found to be responsible for the tumor suppression [104]. Although its etiological role in melanomas was questioned, TRPM1 is a pathogenic factor to cause the autosomal recessive congenital stationary night blindness type 1C (CSNB1C) (OMIM 613216), a clinically and genetically heterogeneous group of retinal disorders. CSNB1C is characterized by nonprogressive impaired night vision and decreased visual acuity. On ON bipolar cells, TRPM1 channels are gated by the mGluR6 (GRM6) signaling cascade, and their opening is necessary for the depolarization evoked by light stimulation. The mutant channels show decreased light response, which causes the dysfunction of both rod and cone ON bipolar cells of the mammalian retina [105–110]. The same disease was discovered in the Appaloosa horse where CSNB was associated with coat spotting pattern. Although human patients also display myopia, reduced central vision, and nystagmus, unlike the Appaloosa horses and the anticipated TRPM1 function in melanocytes, none of the patients show abnormal skin pigmentation [111]. A DNA microdeletion involving, among else, the TRPM1 gene was found to cause a syndrome with severe central nervous system dysfunction, including mental retardation, extrapyramidal symptoms, refractory epilepsy, and encephalopathy. This deletion syndrome is also associated with congenital retinal dysfunction, suggested to be caused by the loss of TRPM1 [112].

TRPM2 and TRPM7, two chanzymes (i.e., ion channels that also possess enzymatic functions), have been suspected for a long time to cause the Guamanian amyotrophic lateral sclerosis (ALS-G) and Parkinsonism dementia-Guam (PD-G, or Parkinsonism dementia complex, PDC) (OMIM 105500), two related neurodegenerative disorders that are endemic on the Western Pacific (including Guam) [113]. Although ALS-G and PD-G have a multifactorial etiology involving special mineral composition of the soil and drinking water, as well as the presence of putative neurotoxin, l-beta-N-methylamino-l-alanine, derived from the traditionally consumed cycad plant, mutations in the TRPM2 and TRPM7 genes were identified in a subset of ALS-G and PD-G patients. These mutations resulted in a decreased channel activity in physiological circumstances, which, in the presence of the environmental triggers, may contribute to the pathomechanism of these diseases via decreased intracellular Mg^2 + concentration ([114–116]; for a review, see Refs. [117,118]). However, a recent linkage analysis did not reveal any evidence in support of the linkage to the TRPM7 locus, indicating that at least TRPM7 is not associated with ALS-G/PDC [119].

TRPM2 has been implicated in various forms of bipolar disorder or psychosis maniaco-depressiva. One of the putative susceptibility locus of the bipolar disorder type I (BD-I), the “classical” form of the disease characterized by manic or mixed episodes usually alternating with major depressive episodes, is located in the TRPM2 encoding chromosomal region [120–122]. Furthermore, SNPs in the promoter region of TRPM2 are also linked to BD-II, in which form the maniac episodes are less dominant [123]. Most recently, a novel TRPM2 mutation (R755C) has been discovered in Crohn’s disease [124].

TRPM3 might possess the most transcript variants among TRP channels potentially resulting in functionally different channels [125], but the relations to genetic diseases have not been characterized, yet. TRPM3 has been recently discussed as a part of the genetic background for the comorbidity between autism and muscular dystrophy Duchenne. Indeed, in some patients simultaneously suffering from both diseases, a deletion involving exons 1-9 of TRPM3 has been described [126]. TRPM3 is coded in a genetic locus that might be involved in the pathogenesis of the Kabuki syndrome (OMIM 147920), a multiple congenital mental retardation syndrome characterized by distinct facial appearance, heart defects, urinary tract anomalies, hearing loss, hypotonia, short stature, joint laxity, and unusual dermatoglyphic patterns [127]. TRPM3 SNPs located in the splicing sites have been discovered in patients with metabolic syndrome and diabetes type 2 [128]. TRPM3 is also often mentioned as a gene involved in developmental failures of the vertebrate lens, which process is probably regulated by the miRNA204 coded in the intron 8 of the TRPM3 gene [129,130].

TRPM4 mutations are responsible for the development of the autosomal dominant progressive familial heart block type I (OMIN 113900), a progressive cardiac bundle branch disease in the His-Purkinje system. The disease-causing mutation E7K leads to a gain-of-function phenotype, probably due to an increased surface expression. This increased activity can lead to depolarization-induced defects in the conductive system and generate electrical gridlock [131,132]. Mutations were also identified in patients with atrioventricular block, but no mutations were found in other patients with sinus node dysfunction, Brugada syndrome, or long-QT syndrome [133]. It is still debated whether TRPM4 plays a genetic role in alteration of the arterial myogenic response (Bayliss effect) associated with stroke, cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy [134]. Recently, four TRPM4 mutants were described in patients with Brugada syndrome, which is characterized by a bifascicular block or a complete right bundle branch block. Two of the four mutants (P779R and K914X) resulted in a decreased expression, whereas the other two (T873I and L1075P) increased the expression of TRPM4 channels [135]. In the last year, a possible role of TRPM4 in multiple sclerosis has also been described [136].

TRPM5 has not been linked to any channelopathy yet. However, an SNP in the TRPM5 gene was associated with decreased risk of childhood leukemia [137].

TRPM6, like TRPV4, is also a hot spot of hereditary mutations leading to channelopathies. The channel has a key role in Mg^2 + (re)absorption both in the intestines and kidney; therefore, its mutations result mostly in diseases associated with disturbances in Mg^2 + homeostasis. More than 35 mutations in the TRPM6 gene have been described, causing the autosomal recessive disease hypomagnesemia with secondary hypocalcemia 1 (HSH1 or, HOMG1) (OMIM 602014) [138,139]. The leading symptoms of HSH1 are the very low serum levels of Mg^2 + and Ca^2 +. It is diagnosed generally during the first 6 months of life, based on the characteristic secondary neurological symptoms. The primary defect is a decreased renal/intestinal Mg^2 + reabsorption and the consecutively lowered parathyroid hormone (PTH) secretion by the parathyroid gland. The decrease in PTH and consequently also in serum Ca^2 + levels (secondary hypocalcemia) result in generalized seizures, tetany, and muscle spasms, which are resistant to conventional anticonvulsive therapies. Without treatment, the disease leads to severe mental retardation or death. Successful causal therapies are based on the replenishment of the blood Mg^2 + level, using intravenous Mg^2 + application first, which has to be followed by lifelong high-dose oral Mg^2 + supplementation. The overdosed Mg^2 + increases the renal Mg^2 + reabsorption via a paracellular pathway in the thick ascending limb of the loop of Henle, which has a lesser importance in healthy individuals, where the major part of the Mg^2 + reabsorption occurs via TRPM6 expressed in the distal convoluted tubule. The disease-causing mutations in TRPM6 result in a loss-of-function phenotype. It mostly results from a truncated protein because introduction of stop codons, although single-point mutations, frameshift mutations, exon splicing, deletions and mutations affecting alternative splicing, as well as a pore mutation have been also described (for reviews and recent new mutations, see Refs. [4,140–142]). This form of hypomagnesaemia, which has to be separated from other forms (like HOMG2-6), caused mutations in other genes different from TRPM6. Beyond HSH1, TRPM6 deletion has been described in a patient with epilepsy and intellectual disorder [143], and two genetic variants (V1393I and K1584E) have been identified in diabetes 2 patients [144].

TRPM8 is not linked to any distinct channelopathy yet. However, the pathomechanism of familial amyloid polyneuropathy (or familial amyloidotic neuropathy, neuropathic heredofamilial amyloidosis, familial amyloid polyneuropathy), a rare group of autosomal-dominant neuropathies of autonomic and peripheral nerves, might involve TRPM8 [145]. Recently, SNPs in TRPM8 have been connected to hereditary forms of migraine [146,147]. The dry eye syndrome seems also to be related to TRPM8 dysfunction, but any hereditary evidence is still missing [148].

TRPA Channelopathies

Transient receptor potential ankyrin 1 (TRPA1) mutation causes a painful channelopathy, the familial episodic pain syndrome 1 (FEPS1) (OMIM 615040). This is a rare autosomal-dominant disease. In affected patients, fasting and physical stress trigger episodes of debilitating upper body pain. The symptoms also involve enhanced cutaneous flare responses and secondary hyperalgesia to punctate stimuli. One point mutation was identified that causes an amino acid substitution (N855S) in the S4 voltage-sensing domain. Although its pharmacological profile is not altered, the mutant is characterized by a shift in gating properties; its activity is much higher at normal resting potential, resulting in a dramatic increase of inward currents. In vitro, specific TRPA1 antagonists inhibited the abnormal response of the mutant channel, which promises a potential cure for patients suffering from FEPS1 ([149,150]; see, for a recent review, Ref. [151]). Recently, a missense point mutation has been discovered in pain patients with paradoxical heat sensation, which causes the E179K substitution in the TRPA1 N-terminus [152]. Cold failed to activate the mutant channel, probably because of a disturbed interaction with associated proteins [153].

TRPML Channelopathies

TRPML1, the funding member of the mucolipidosis subfamily of the TRP channels, was named after the channelopathy, mucolipidosis type IV (ML IV, ML4) (OMIM 252650), caused by mutations in the TRPML1 gene. ML4 is an autosomal recessive neurodegenerative disease with a lysosomal storage disorder background. The leading neurological and sensory symptoms are psychomotor retardation and ophthalmologic abnormalities. The latter include corneal opacity, retinal degeneration, and strabismus, but developmental defect of the corpus callosum was also found. Furthermore, blood iron deficiency and achlorhydria also characterize ML4 patients, whose majority belongs to the Ashkenazi Jews population [154–156]. Over 21 mainly loss-of-function mutations in TRPML1 have been identified in ML4 patients. Defects of channel function result in impaired Ca^2 + release from the organelles, which is required for the correct order of cellular events involving membrane fusion/fission ([157]; for a recent review, see Ref. [158]). These malfunctions lead to lysosomal storage disease in which cells are unable to process the material captured during endocytosis, although in contrast to most storage diseases, the function of lysosomal hydrolases is normal in ML4. The pathomechanism involves a defect in transport along the endosomal/lysosomal pathway, affecting membrane sorting, fusion of both endosomes and autophagosomes with lysosomes (for a review, see Ref. [159]). Defects in the late steps of endocytosis and autophagy cause intracellular accumulation of lysosomal substrates and formation of large vacuolar intracellular organelles containing amphiphilic lipids (phospholipids, sphingolipids, gangliosides, mucopolysaccharides, lipofucsins, etc.) and other materials from cell organelle debris [160,161]. Moreover, TRPML1 also functions as a Fe^2 + and Zn^2 + channel, which is important in the removal of these ions from the lysosomes. In the absence of this lysosomal Fe^2 +/Zn^2 + leak in ML4, lysosomes can be overloaded with these heavy metals, leading to the further impairment of lysosomal functions [162]. Another lipid-storage disease, the Niemann-Pick type C disease (NPC) (OMIM 257220) is primarily caused by mutations in the lysosomal two-pore segment channel 1, but like ML4, it also shows dramatically reduced TRPML1-mediated lysosomal Ca^2 + release. Sphingomyelins (SMs) undergo sphingomyelinase-mediated hydrolysis in normal lysosomes, but they are accumulated in lysosomes of cells of NPC patients. SMs were found to inhibit TRPML1 in vitro, and abnormal luminal accumulation of these lipids can also block TRPML1- and Ca^2 +-dependent lysosomal trafficking causing a secondary lysosome storage disorder [163,164].

TRPML3 mutation is responsible for the phenotype of the varitint-waddler mouse, characterized by deafness and altered fur pigmentation [165]. However, neither TRPML2 nor TRPML3 has been reported to cause human diseases yet.

TRPP Channelopathies

The nomenclature of TRP channels in the polycystin (TRPP) family is still somewhat confusing due to the reclassification of some members. Although a recently suggested nomenclature numbers the “real” TRPP channels consecutively from TRPP1 to TRPP3 [166], in this review we still use the official HUGO nomenclature to prevent further confusions and remain consequent with most of the cited literature. In the TRPP family, we can find only three ion channels: (1) TRPP2 (in the new nomenclature TRPP1 but also known as PKD2), (2) TRPP3 (now TRPP2 or PKD2 like 1 (PKD2L1)), and (3) TRPP5 (now TRPP3 or PKD2L2). These real TRP channels, as well as the reclassified nonchannel members, have a strong relationship to polycystic kidney disease, which gave the name polycystin to the family.

TRPP2 mutations are common causes of autosomal-dominant polycystic kidney disease (ADPKD) (OMIM 613095). The most characteristic symptom of this disease is the progressive development of large epithelial-lined cysts not only in the kidney but also in the liver, pancreas, seminal tract, and arachnoid membrane. In the kidneys, any segment of the nephron can be affected by formation of cysts. Developing cysts press the renal parenchyma, further increasing the circumference of the already dilated renal tubules. As they are growing, cysts occupy more and more space and thereby compress and destroy normal renal tissue, resulting in abnormally enlarged kidneys and impaired kidney function. Well-developed cysts are filled with fluid that is probably secreted by the epithelial cells of the cysts. Beside the kidney symptoms, ADPKD also causes cardiovascular abnormalities (e.g., coronary artery aneurysms or intracranial “berry” aneurysms), which often lead to vessel rupture, resulting in potentially fatal acute bleeding or chronic subdural hematomas [167]. Defects in the heart (e.g., defective septum formation) are also known consequences of TRPP2 mutations [168]. Mutations in PKD1 (formerly, TRPP1) and in TRPP2 (ca. 85% and 15% of the cases, respectively) are the major cases of ADPKD; more than 400 mutations in these genes have been described in ADPKD patients [169]. However, the exact pathomechanism and the contribution of PKD1 and TRPP2 to the pathophysiology of the polycystic kidney disease are largely unknown (for an excellent review, see Ref. [170]). TRPP2 was hypothesized to function as a putative flow-sensor in the primary cilia; to fulfill this role, it needs to associate with PKD1 forming the polycystin complex (for a review, see Ref. [171]). TRPP2 is involved in the regulation of cellular processes via several crucially important signaling pathways, like the JAK/STAT, p53, mTOR, NFAT/AP-1, cAMP/PKA, cAMP-dependent ERK, cyclin-dependent kinases, or Wnt signaling pathways. All these pathways may be partially involved in the pathogenesis of ADPKD (for a review, see Ref. [172]). The disturbed connections of the mutant channel proteins with cytoskeletal interaction partners may also result in functional defects [173]. The complex of PKD1 with TRPP2 also prevents the nuclear translocation of a crucial regulator of cell proliferation and differentiation, the helix-loop-helix protein Id2. In patients with PKD1/TRPP2 mutations, Id2 accumulates in the nuclei of the renal epithelial cells to constitute a hyperproliferative phenotype, causing cyst formation [174,175]. Because ADPKD is a ciliopathy, an association of TRPP2 with other ciliopathies is also expected. In two sisters suffering from Joubert syndrome, a rare genetic disorder affecting the cerebellum and manifesting in balance and coordination disturbances, mutation of TCTN1 gene was identified. The translated protein Tectonic-1 is a regulator of the ciliogenesis, and it forms a complex with many ciliar proteins. Furthermore, it is needed for the correct ciliar localization of TRPP2 [176]. Another example is Meckel syndrome (also known as Meckel-Gruber syndrome, Gruber syndrome, or dysencephalia splanchnocystica), a rare, lethal, genetic ciliopathy. In a rat model of Meckel syndrome, significantly increased TRPP2 protein expression was found [177]. Interestingly, TRPP2 mutations can also lead to impaired morphogenesis; these mutations are reportedly involved in the deformation of the left-right lateralization due to a primary ciliar dyskinesia [178,179].

TRPP3 (earlier PKD2L1) is also needed for normal ciliar functions. It has been recently identified in primary cilia as a component (together with PKD1L1) of a Ca^2 + permeable cation channel. This complex played a role in the regulation of GLI2 by smoothened protein, elements of the hedgehog pathway. TRPP3-PKD1L1 channels play an important role in the regulation of the Ca^2 + concentration in a subciliar compartment [180,181]. Based on the literature, it is intriguing to hypothesize that TRPP3 (PKD2L1) may play an important role in neurodevelopmental disorders and ciliopathies (see for a review, Ref. [182]).

Conclusions