HGNC Approved Gene Symbol: TRPM4
SNOMEDCT: 698250005;
Cytogenetic location: 19q13.33 Genomic coordinates (GRCh38) : 19:49,157,792-49,211,836 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 19q13.33 | Erythrokeratodermia variabilis et progressiva 6 | 618531 | Autosomal dominant | 3 |
| Progressive familial heart block, type IB | 604559 | Autosomal dominant | 3 |
TRPM4 belongs to the melastatin (TRPM1; 603576)-related transient receptor (TRPM) channel family. TRPMs are Ca(2+)-permeable cation channels localized predominantly to the plasma membrane. The structural machinery of TRPM channels includes intracellular N and C termini, 6 transmembrane segments, and a pore region between segments 5 and 6. The N-terminal domain has a conserved region, and the C-terminal domain contains a TRP motif, a coiled-coil region, and, in some TRPM channels, an enzymatic domain. TRPM4 is a mediator of pressure-induced membrane depolarization and arterial constriction (review by Farooqi et al., 2011).
By searching an EST database and screening brain, testis, and placenta cDNA libraries, Xu et al. (2001) obtained a cDNA encoding TRPM4. The predicted TRPM4 protein has 1,040 amino acids and contains 6 putative transmembrane domains. Northern blot analysis detected TRPM4 expression in most adult tissues tested, with highest levels in heart, prostate, and colon. In fetus, TRPM4 expression was most abundant in kidney. There were at least 2 distinct bands detected (6.2 and 4.2 kb), indicating alternative splicing of TRPM4. In addition, a smaller but relatively abundant 2.4-kb transcript was detected in testis.
Launay et al. (2002) cloned and characterized a second form of TRPM4. The predicted 1,214-amino acid protein is nearly identical to the protein reported by Xu et al. (2001), except that it includes an additional 174 amino acids N-terminal to the predicted start of that protein. The shorter protein results from alternative splicing, with the third and fourth exons being spliced out and the beginning of the first exon being truncated. As a consequence, the first in-frame methionine lies in the fifth exon, resulting in the deletion of the first 174 amino acids. Launay et al. (2002) proposed that the shorter protein be designated TRPM4a and the longer protein be designated TRPM4b.
Kruse et al. (2009) performed quantitative analysis of TRPM4 mRNA content in human cardiac tissue and found the highest expression level in Purkinje fibers.
By immunohistochemistry on sections of bovine hearts, Liu et al. (2010) demonstrated that TRPM4 channel signal level is higher in atrial cardiomyocytes than in ventricular cells, but is highest in Purkinje fibers. Small bundles of highly TRPM4-positive cells were found in the subendocardium and in rare intramural bundles.
By RT-PCR, Wang et al. (2019) detected TRPM4 mRNA expression in the epidermis from normal dorsal foot skin and in the human epidermal keratinocyte cell line HaCaT.
Crystal Structure
Winkler et al. (2017) reported the electron cryomicroscopy structure of the most widespread human Ca2(+)-activated, nonselective (CAN) channel, TRPM4, bound to the agonist Ca(2+) and the modulator decavanadate. Four cytosolic C-terminal domains form an umbrella-like structure with a coiled-coil domain for the 'pole' and 4 helical 'ribs' spanning the N-terminal TRPM homology regions (MHRs), thus holding 4 subunits in a crown-like architecture. Winkler et al. (2017) observed 2 decavanadate-binding sites, 1 in the C-terminal domain and another in the intersubunit TRPM homology region interface. A glutamine in the selectivity filter may be an important determinant of monovalent selectivity.
Guo et al. (2017) presented the electron cryomicroscopy structures of the mouse TRPM4 channel with and without ATP. TRPM4 consists of multiple transmembrane and cytosolic domains, which assemble into a 3-tiered architecture. The N-terminal nucleotide-binding domain and the C-terminal coiled-coil participate in the tetrameric assembly of the channel; ATP binds at the nucleotide-binding domain and inhibits channel activity. TRPM4 has an exceptionally wide filter but is permeable only to monovalent cations; filter residue gln973 is essential in defining monovalent selectivity. The S1-S4 domain and the post-S6 TRP domain form the central gating apparatus that probably houses the Ca(2+)- and phosphatidylinositol-4,5-bisphosphate-binding sites.
Cryoelectron Microscopy
Autzen et al. (2018) presented 2 structures of full-length human TRPM4 embedded in lipid nanodiscs at approximately 3-angstrom resolution, as determined by single-particle cryoelectron microscopy. These structures, calcium-bound and -unbound, revealed a general architecture for this major subfamily of TRP channels and a well-defined calcium-binding site within the intracellular side of the S1-S4 domain. The structures corresponded to 2 distinct closed states. Autzen et al. (2018) concluded that calcium binding induces conformational changes that likely prime the channel for voltage-dependent opening.
By genomic sequence analysis, Xu et al. (2001) mapped the TRPM4 gene to chromosome 19q13.32.
Xu et al. (2001) showed that TRPM4 mediates Ca(2+) entry when expressed in HEK293 cells.
Launay et al. (2002) showed that TRPM4b encodes a cation channel that is directly activated by intracellular calcium concentration. They found that it conducts monovalent cations such as sodium and potassium without significant permeation of Ca(2+). TRPM4b is activated following receptor-mediated Ca(2+) mobilization, representing a regulatory mechanism that controls the magnitude of Ca(2+) influx by modulating the membrane potential and, with it, the driving force for Ca(2+) entry through other Ca(2+)-permeable pathways.
Launay et al. (2004) showed that the molecular inhibition of endogenous TRPM4 in T cells suppresses TRPM4 currents, with a profound influence on receptor-mediated calcium mobilization. Agonist-mediated oscillations in intracellular Ca(2+) concentration, which are driven by store-operated Ca(2+) influx, were transformed into a sustained elevation in intracellular Ca(2+) concentration. This increase in Ca(2+) influx enhanced interleukin-2 (147680) production. Thus, Launay et al. (2004) concluded that TRPM4-mediated depolarization modulates calcium oscillations, with downstream effects on cytokine production in T lymphocytes.
Using rat and mouse models, Gerzanich et al. (2009) found that Trpm4 had a pivotal role in the development of secondary hemorrhage following spinal cord injury. Trpm4 was expressed at low levels in uninjured rats. Following spinal cord injury, Trpm4 expression was upregulated in tissues surrounding the injury and extended to distant tissues, including the contralateral hemicord. In situ hybridization confirmed that Trpm4 was upregulated after injury, especially in microvessels in the penumbra. Work with cell cultures suggested that severe ATP depletion associated with spinal cord injury caused sustained Trpm4 channel opening, followed by depolarization, continuous cation influx, oncotic swelling, and oncotic cell death, resulting in capillary fragmentation and hemorrhage. Blocking Trpm4 expression in rats via treatment with antisense RNA or loss of Trpm4 expression in Trpm4 -/- mice reduced secondary hemorrhage and greatly improved lesional and behavioral outcome after spinal cord injury.
Yan et al. (2020) found that the NMDAR subunits Grin2a (138253) and Grin2b (138252) formed a complex with Trpm4 in cultured mouse neurons and mouse brain. The interaction was mediated by a 57-amino acid intracellular domain of Trpm4, termed TwinF, that was positioned just beneath the plasma membrane. TwinF interacted with I4, an evolutionarily conserved stretch of 18 amino acids containing 4 regularly spaced isoleucines located within the intracellular, near-membrane portion of Grin2a and Grin2b. The NMDAR/Trpm4 complex could be disrupted by expression of TwinF, which competed with endogenous Trpm4 for binding to Grin2a and Grin2b, or through the use of small-molecule NMDAR/Trpm4 interaction interface inhibitors that Yan et al. (2020) identified in a computational compound screen. These interface inhibitors strongly reduced NMDA-triggered toxicity and mitochondrial dysfunction, abolished CREB shutoff, boosted gene induction, and reduced neuronal loss in mouse models of stroke and retinal degeneration.
Progressive Familial Heart Block, Type IB
In an Afrikaner kindred with progressive heart block mapping to chromosome 19q13.3 (PFHB1B; 604559), originally reported by Brink and Torrington (1977), Kruse et al. (2009) analyzed the candidate gene TRPM4 and identified a heterozygous missense mutation (E7K; 606936.0001) that segregated with the disease. Cellular expression studies showed that the mutation attenuated deSUMOylation of the TRPM4 channel, resulting in impaired endocytosis and elevated TRPM4 channel density at the cell surface. Kruse et al. (2009) concluded that this type of familial heart block is thus caused by a gain-of-function mechanism.
In a large Lebanese kindred and 2 French families with autosomal dominant cardiac conduction defects mapping to chromosome 19q13, Liu et al. (2010) analyzed 12 candidate genes and identified 3 heterozygous missense mutations in the TRPM4 gene (606936.0002-606936.0004) that were found in all affected family members. The mutations were also detected in several family members with incomplete right bundle branch block (RBBB) or no block; penetrance was calculated to be 75% for males and 54% for females. All 3 mutations resulted in gain of function due to increased channel density at the cell surface secondary to impaired endocytosis and deregulation of SUMOylation.
Stallmeyer et al. (2012) analyzed the TRPM4 gene in 160 unrelated patients with various types of inherited cardiac arrhythmias and identified 8 missense mutations in 8 patients (see, e.g., 606936.0002 and 606936.0004-606936.0006), including 5 (26.3%) of 19 patients with RBBB and 3 (11.5%) of 26 patients with atrioventricular (AV) block. No mutations were identified in patients with other types of cardiac arrhythmias. Noting the phenotypic variability in the mutation-positive patients, Stallmeyer et al. (2012) suggested that additional factors might modulate the disease phenotype in some patients.
Erythrokeratodermia Variabilis et Progressiva 6
In affected members of 2 unrelated 4-generation Chinese families segregating autosomal dominant progressive symmetric erythrokeratodermia (EKVP6; 618531), Wang et al. (2019) identified heterozygosity for a missense mutation in the TRPM4 gene (I1040T; 606936.0007). In a sporadic patient with EKVP, they identified heterozygosity for a de novo missense mutation in TRPM4 (I1033M; 606936.0008). None of the affected individuals reported symptoms of cardiac arrhythmias or history of cardiac disorders, and no arrhythmias were detected on repeated electrocardiograms in 3 affected individuals. Electrophysiologic analysis indicated that both mutations represented gain-of-function TRPM4 variants.
Associations Pending Confirmation
Janin et al. (2019) studied a 64-year-old man with exertional dyspnea, hypertension, chronic kidney disease, coronary disease, and an electrocardiogram showing complete right bundle branch block as well as a Brugada type 1-like pattern (see 601144) with ST segment elevation in leads V1 and V2. Analysis of a panel of 19 Brugada syndrome-associated genes revealed compound heterozygosity for a splicing mutation (c.1150+1G-A) in intron 9 and a nonsense mutation (W525X) in exon 11. The variants were present in the gnomAD database with minor allele frequencies of 0.0032% and 0.15%, respectively.
To test the importance of calcium-activated nonselective cation channels, Vennekens et al. (2007) generated viable and fertile Trpm4 -/- mice. Trpm4 -/- mast cells had more Ca(2+) entry after stimulation of Fcer1 (see 147140) than did wildtype mast cells. Consequently, Trpm4 -/- mast cells had augmented degranulation and released more histamine, leukotriene, and Tnf (191160). Trpm4 -/- mice had more severe acute, but not late-phase, passive cutaneous anaphylaxis than wildtype mice. Vennekens et al. (2007) concluded that TRPM4 channels are critical regulators of Ca(2+) entry in mast cells.
In affected members of an Afrikaner kindred with progressive heart block mapping to chromosome 19q13.3 (PFHB1B; 604559), originally reported by Brink and Torrington (1977), Kruse et al. (2009) identified heterozygosity for a 19G-A transition (c.19G-A, NM_017636) in exon 1 of the TRPM4 gene, predicting a glu7-to-lys (E7K) substitution at an evolutionarily conserved residue within the N terminus. The mutation was not found in unaffected family members, in 230 ancestry-matched, unrelated Afrikaner controls, or in 389 unrelated individuals of mixed European descent. The mutant channel displayed normal gating properties; however, the E7K channel was present at increased density in the plasma membrane due to attenuated channel deSUMOylation, a previously unknown mechanism in the etiology of cardiac channelopathies.
In affected individuals from a large Lebanese kindred segregating autosomal dominant cardiac conduction defects (PFHB1B; 604559), originally described by Stephan (1978), Liu et al. (2010) identified heterozygosity for a 1294G-A transition (c.1294G-A, ENST00000252826) (as noted in their Figure 3) in exon 11 of the TRPM4 gene, resulting in an ala432-to-thr (A432T) substitution at a highly conserved residue in the cytoplasmic N terminus. The mutation was also detected in several family members with incomplete right bundle branch block (RBBB) or no block, consistent with incomplete penetrance, but was not found in 300 ethnically matched control chromosomes. Functional analysis in HEK293 cells demonstrated that current amplitudes were dramatically elevated for mutant versus wildtype channels, despite no increase in Ca(2+) affinity for the mutant channels compared to wildtype. Quantitative analysis of transfected COS-7 cells revealed that the gain of function was due to increased density of mutant channels at the cell surface, which was found to result from impaired endocytosis and deregulation of SUMOylation.
In a 38-year-old Turkish man with first-degree atrioventricular conduction block and atypical RBBB, Stallmeyer et al. (2012) identified compound heterozygosity for the A432T mutation and a 1744G-A transition in the TRPM4 gene, resulting in a gly582-to-ser (G582S) substitution (606936.0005) that was not found in 670 European or 154 Turkish control samples. In addition, he carried a polymorphic in-frame deletion (2283-2294del, resulting in R762-G765del). His father and a sister had both died suddenly due to cardiac arrhythmias of unknown origin.
Xian et al. (2018) found that plasma membrane expression levels of human TRPM4 with the A432T mutation were 50% lower in HEK293 cells, but the relative membrane current was more than 2-fold larger, compared with wildtype TRPM4. Kinetic analysis showed that TRPM4-A432T had 4-fold slower calcium-dependent deactivation than wildtype. Analysis with human induced pluripotent stem cell-derived cardiac myocytes revealed that TRPM4-A432T also generated excessive membrane currents during cardiac action potentials. The authors demonstrated that altered deactivation of TRPM4-A432T was not due to alterations in glycosylation, phosphorylation, or plasma membrane phosphatidylinositol 4,5-bisphosphate levels. Instead, site-directed mutagenesis and structural modeling showed that replacement of the nonpolar, small-side-chained ala432 with a bulky threonine changed the compactness of the channel subdomain in TRPM-A432T.
In affected individuals from a French family segregating autosomal dominant cardiac conduction defects (PFHB1B; 604559), Liu et al. (2010) identified heterozygosity for a 490C-T transition (c.490C-T, ENST00000252826) (as noted in their Figure 3) in exon 5 of the TRPM4 gene, resulting in an arg164-to-trp (R164W) substitution at a highly conserved residue in the cytoplasmic N terminus. The mutation was also detected in several family members with incomplete RBBB or no block, consistent with incomplete penetrance, but was not found in 300 ethnically matched control chromosomes. Functional analysis in HEK293 cells demonstrated that current amplitudes were dramatically elevated for mutant versus wildtype channels, despite no increase in Ca(2+) affinity for the mutant channels compared to wildtype. Quantitative analysis of transfected COS-7 cells revealed that the gain of function was due to increased density of mutant channels at the cell surface, which was found to result from impaired endocytosis and deregulation of SUMOylation.
In affected individuals from a French family segregating autosomal dominant cardiac conduction defects (PFHB1B; 604559), Liu et al. (2010) identified heterozygosity for a 2531G-A transition (c.2531G-A, ENST00000252826) (as noted in their Figure 3) in exon 17 of the TRPM4 gene, resulting in a gly844-to-asp (G844D) substitution at a conserved residue within an intracellular sequence connecting the second and third transmembrane segments. The mutation was also detected in several family members with incomplete RBBB or no block, consistent with incomplete penetrance, but was not found in 300 ethnically matched control chromosomes. Functional analysis in HEK293 cells demonstrated that current amplitudes were dramatically elevated for mutant versus wildtype channels, despite no increase in Ca(2+) affinity for the mutant channels compared to wildtype. Quantitative analysis of transfected COS-7 cells revealed that the gain of function was due to increased density of mutant channels at the cell surface, which was found to result from impaired endocytosis and deregulation of SUMOylation.
In 2 unrelated German patients with right bundle branch block and left anterior hemiblock (LAHB), Stallmeyer et al. (2012) identified heterozygosity for the G844D mutation (c.2531G-A, NM_017636.3) in the TRPM4 gene. One patient was an asymptomatic 11-year-old German boy with RBBB and LAHB but a normal heart rate. His 45-year-old mother, who had a normal electrocardiogram (ECG), also carried the mutation. The other patient was a 17-year-old boy who was compound heterozygous for G844D and a polymorphic in-frame deletion (2283-2294del, resulting in R762-G765del); his ECG showed a 'bizarre and obvious' RBBB and LAHB. His 45-year-old father, who carried the G844D mutation, had a normal ECG, as did his 44-year-old mother, who was a heterozygous carrier of the polymorphism.
For discussion of the 1744G-A transition (c.1744G-A, NM_017636.3) in the TRPM4 gene, resulting in a gly582-to-ser (G582S) substitution, that was found in compound heterozygous state in a patient with first-degree atrioventricular conduction block and atypical right bundle branch block (PFHB1B; 604559) by Stallmeyer et al. (2012), see 606936.0002.
In a Turkish father and son with cardiac conduction defects (PFHB1B; 604559), Stallmeyer et al. (2012) identified heterozygosity for a 2741A-G transition (c.2741A-G, NM_017636.3) in the TRPM4 gene, resulting in a lys914-to-arg (K914R) substitution at a highly conserved residue in the cytoplasmic TM4-TM5 linker. The son presented before 2 years of age with severe congenital third-degree atrioventricular (AV) block, requiring a cardiac pacemaker for bradycardia and follow-up of more than 30 years. His father had a less severe phenotype with asymptomatic right bundle branch block and normal AV conductance. The mutation was not found in the son's asymptomatic daughter or in 738 European or 154 Turkish control samples.
In affected members of 2 unrelated 4-generation Chinese families (families 1 and 2) segregating autosomal dominant progressive symmetric erythrokeratodermia (EKVP6; 618531), Wang et al. (2019) identified heterozygosity for a c.3119T-C transition in the TRPM4 gene, resulting in an ile1040-to-thr (I1040T) substitution at a highly conserved residue within the S6 transmembrane segment, which forms the ion permeation pore. The mutation, which was identified by whole-exome sequencing and confirmed by Sanger sequencing, segregated fully with disease in both families; haplotype analysis indicated that c.3119T-C was a recurrent mutation that arose independently in the 2 families. Electrophysiologic studies in transfected HEK293 cells showed substantial hyperactivity with the I1040T mutant, which exhibited pronounced baseline activity, enhanced sensitivity to intracellular Ca(2+), and an elevated resting membrane potential compared to wildtype. In vitro studies demonstrated enhanced proliferation in keratinocytes overexpressing the I1033M mutant compared to wildtype. Immunochemical analysis of lesional skin from a patient in family 2 showed upregulation of markers for proliferation and differentiation of keratinocytes.
In a Han Chinese girl with progressive symmetric erythrokeratodermia (EKVP6; 618531), Wang et al. (2019) identified heterozygosity for a de novo c.3099C-G transversion in the TRPM4 gene, resulting in an ile1033-to-met (I1033M) substitution at a highly conserved residue within the S6 transmembrane segment, which forms the ion permeation pore. The mutation was not found in her unaffected parents, in BGI in-house databases, or in the 1000 Genomes Project, NHLBI Exome Sequencing Project, or ExAC databases. Electrophysiologic studies in transfected HEK293 cells showed substantial hyperactivity with the I1033M mutant, which exhibited pronounced baseline activity, enhanced sensitivity to intracellular Ca(2+), and an elevated resting membrane potential compared to wildtype. In vitro studies demonstrated enhanced proliferation in keratinocytes overexpressing the I1033M mutant compared to wildtype.
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