Alternative titles; symbols
HGNC Approved Gene Symbol: TMEM43
Cytogenetic location: 3p25.1 Genomic coordinates (GRCh38): 3:14,125,052-14,143,680 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 3p25.1 | Arrhythmogenic right ventricular dysplasia 5 | 604400 | Autosomal dominant | 3 |
| Auditory neuropathy, autosomal dominant 3 | 619832 | Autosomal dominant | 3 | |
| Emery-Dreifuss muscular dystrophy 7, AD | 614302 | Autosomal dominant | 3 |
The TMEM43 gene encodes a highly conserved nuclear envelope protein (Bengtsson and Otto, 2008).
Using a positional cloning approach in a study of 15 families with arrhythmogenic right ventricular cardiomyopathy/dysplasia mapping to chromosome 3 (ARVD5; 604400), Merner et al. (2008) identified TMEM43 as the gene mutated in this disorder. The deduced 400-amino acid TMEM43 protein contains a transactivation domain, 4 transmembrane domains, and putative sites for phosphorylation, O-glycosylation, and sumoylation. TMEM43 also has a putative peroxisome proliferator response element, suggesting that it may be a PPAR-gamma (601487) target gene. Merner et al. (2008) demonstrated that TMEM43 is expressed in both blood and cardiac tissue.
Bengtsson and Otto (2008) found that the TMEM43 protein contains 4 transmembrane domains and a large hydrophilic domain located between membrane spans 1 and 2. The large hydrophilic domain is localized to the lumen of the endoplasmic reticulum and exposed to the perinuclear space, whereas both termini are in the cytoplasm or nucleoplasm. A fraction of TMEM43 is retained at the nuclear envelope and is an integral membrane protein of the inner nuclear membrane.
Liang et al. (2011) found expression of TMEM43 in all examined tissue, including cardiac and skeletal muscle. There was clear nuclear localization. Immunocytochemical studies identified a 43-kD band in total cell lysates and nuclear fractions of HEK, HeLa, and C2 cells. The protein was found to form monomers, dimers, trimers, tetramers, and oligomers.
Merner et al. (2008) determined that the TMEM43 gene contains 12 exons and spans 18.7 kb.
By genomic sequence analysis, Merner et al. (2008) mapped the TMEM43 gene to chromosome 3p25.
Bengtsson and Otto (2008) found that TMEM43 binds A- (LMNA; 150330) and B- (LMNB1; 150340) type lamins and depends on A-type lamins for its inner nuclear membrane localization. The TMEM43 protein was also shown to interact with emerin (EMD; 300384). Downregulation of TMEM43 and overexpression of dominant-negative acting TMEM43 caused redistribution of emerin. The findings suggested that TMEM43 functions as a nuclear membrane organizer.
Liang et al. (2011) demonstrated that TMEM43 interacts with SUN2 (613569), another inner nuclear membrane protein.
Using coimmunoprecipitation and proximity ligation assays in HEK293 cells, Jang et al. (2021) demonstrated that TMEM43 interacts with TASK1 (KCNK3; 603220). By deleting specific regions of TMEM43 and studying the interaction with TASK1, Jang et al. (2021) determined that the Loop1 intracellular loop of TMEM43 is necessary for TASK1 interaction. In vitro studies in mouse cochlear cells determined that TASK1 preferentially interacts with the posttranslationally modified form of TMEM43 (60 Kd).
Arrhythmogenic Right Ventricular Dysplasia 5
In 83 affected individuals with arrhythmogenic right ventricular dysplasia-5 (604400) from 15 unrelated Newfoundland families, Merner et al. (2008) identified heterozygosity for a missense mutation (S358L; 612048.0001) in the TMEM43 gene that was not found in 47 spouses or 161 controls.
In an analysis of the TMEM43 gene in 55 Danish probands who fulfilled the criteria for ARVD and 10 patients with only some features of ARVD, Christensen et al. (2011) identified 1 woman fulfilling the criteria who carried the S358L variant.
In DNA samples from 195 unrelated individuals with suspected ARVD, Baskin et al. (2013) identified 6 patients who carried the S358L 'Newfoundland' mutation in TMEM43, including a 43-year-old New Zealand man who was not of Newfoundland descent. In addition, 5 patients carried 5 different rare sequence variants in the TMEM43 (see, e.g., 612048.0004), 2 of whom also carried a variant in the PKP2 and DSP genes, respectively.
Emery-Dreifuss Muscular Dystrophy 7
Based on the putative role for TMEM43 in the nuclear envelope, Liang et al. (2011) analyzed the TMEM43 gene in 41 patients with Emery-Dreifuss muscular dystrophy (EDMD) who were negative for mutations in known EDMD-related genes and identified different heterozygous missense mutations in 2 unrelated individuals (612048.0002 and 612048.0003); see EDMD7 (614302).
Auditory Neuropathy, Autosomal Dominant 2
In 5 members of 3 generations of a Han Chinese family (HN66) and 10 members of 4 generations of a Korean family (SB162) with autosomal dominant auditory neuropathy-3 (AUNA3; 619832), Jang et al. (2021) identified a heterozygous nonsense mutation in the TMEM43 gene (R372X; 612048.0005). The mutation was found by a combination of linkage analysis, whole-exome sequencing, and Sanger sequencing. All of the patients had progressive hearing loss characterized by the inability to discriminate speech with preserved sensitivity to sound.
Jang et al. (2021) found that mouse models heterozygous or homozygous for an R372X mutation (612048.0005) in the Tmem43 gene demonstrated progressive hearing loss and abnormal passive conductance current from glia-like supporting cells (GLSs) in the organ of Corti of the inner ear. On microscopic examination, apical surfaces of the GLSs at the inner border of the organ of Corti from mice with the heterozygous R372X mutation were narrower compared to wildtype mice starting at 7 months of age.
In affected individuals with arrhythmogenic right ventricular dysplasia (ARVD5; 604400) from 15 unrelated Newfoundland families, Merner et al. (2008) identified heterozygosity for a 1073C-T transition in the TMEM43 gene, resulting in a ser358-to-leu (S358L) substitution at a highly conserved residue within the third predicted transmembrane domain. The mutation was not found in 47 spouses or 161 controls. Of 61 'unaffected' individuals who carried the mutation, 35 (57%) were found to have clinical signs of ARVD on subsequent testing, and penetrance was 100% in mutation-positive males and females at ages 63 and 76 years, respectively.
In a Danish woman and her affected mother with ARVD, Christensen et al. (2011) identified heterozygosity for the S358L mutation in the TMEM43 gene. The mutation was not found in the proband's unaffected sister or in 650 ethnically matched controls. The proband became symptomatic at 49 years of age and was diagnosed based on the presence of ventricular tachycardia (VT), T-wave inversion in leads V1 to V5, late potentials on signal-averaged ECG, dilated right ventricle, and fibrofatty infiltrations on endomyocardial biopsy. Her mother, who was subsequently diagnosed at 70 years of age, had similar findings except that biopsy showed fatty infiltrations but no fibrosis. Both patients had normal left ventricular diameter and function. Immunostaining of patient myocardium for TMEM43 showed localization to the sarcolemma, with reduced signal in the patients compared to controls; similar immunostaining for plakoglobin (JUP; 173325) also showed reduced signal, suggesting that TMEM43-associated ARVD shares a final common pathway with desmosome-associated ARVD.
Baskin et al. (2013) identified the TMEM43 S358L 'Newfoundland' mutation in 6 patients, including a 43-year-old New Zealand man who was not of Newfoundland descent. The mutation, which occurred de novo in the New Zealand patient, arose on a different haplotype from that of the patients from Newfoundland, suggesting that S358 might represent a hotspot for sequence alteration.
In a Japanese man with Emery-Dreifuss muscular dystrophy-7 (EDMD7; 614302), Liang et al. (2011) identified a heterozygous 235G-A transition in the TMEM43 gene, resulting in a glu85-to-lys (E85K) substitution in a relatively well-conserved residue in the hydrophilic domain. The mutation was not found in 100 controls. The patient developed symptoms in his forties, and muscle biopsy showed marked fiber size variation with scattered internal nuclei. He died soon after diagnosis. His son reportedly had similar symptoms, suggesting autosomal dominant inheritance, but the son was lost to follow-up. TMEM43 immunostaining detected low protein levels around the nuclei of skeletal muscle. The mutant protein formed predominantly monomers with very few dimers, indicating a defect in oligomerization. Immunoprecipitation studies showed that the mutant protein could still properly interact with emerin and SUN2, but overexpression in HeLa cells resulted in abnormal nuclear structure and decreased nuclear localization of both emerin and SUN2, with mislocalization of emerin to the endoplasmic reticulum. However, mislocalization of emerin and SUN2 was not observed in patient cells.
In a 68-year-old Japanese woman with Emery-Dreifuss muscular dystrophy-7 (EDMD7; 614302), Liang et al. (2011) identified a heterozygous 271A-G transition in the TMEM43 gene, resulting in an ile91-to-val (I91V) substitution in a relatively well-conserved residue in the hydrophilic domain. The mutation was not found in 100 controls. She developed slowly progressive muscle weakness and atrophy of the proximal muscles at age 64, and had a pacemaker implanted due to atrial fibrillation with bradycardia. Muscle biopsy showed necrosis and regeneration. The mutant protein was able to form oligomers. Immunoprecipitation studies showed that the mutant protein could still properly interact with emerin and SUN2, but overexpression in HeLa cells resulted in abnormal nuclear structure and decreased nuclear localization of both emerin and SUN2, with mislocalization of emerin to the endoplasmic reticulum. However, mislocalization of emerin and SUN2 was not observed in patient cells. Overexpression of this mutation in mouse tibialis anterior muscle also caused decreased nuclear localization of emerin.
In a man with arrhythmogenic right ventricular dysplasia (ARVD5; 604400), Baskin et al. (2013) identified heterozygosity for a c.169G-A transition in exon 3 of the TMEM43 gene, resulting in an ala57-to-thr (A57T) substitution at an evolutionarily conserved residue. The mutation was not found in 427 controls. The patient presented with exercise-induced ventricular tachycardia that was too fast for ablation treatment, and he underwent placement of an implantable cardioverter-defibrillator. Electrocardiographic (ECG) abnormalities included anterior T-wave inversion as well as right ventricular enlargement and dysfunction, which was confirmed on CT scan. Voltage map demonstrated reduced endocardial right ventricular voltages consistent with ARVD.
In 15 individuals from 2 unrelated families, a Han Chinese family (HN66) and a Korean family (SB162), with autosomal dominant auditory neuropathy-3 (AUNA3; 619832), Jang et al. (2021) identified a heterozygous c.1114C-T transition (c.1114C-T, NM_024334) in the TMEM43 gene, resulting in an arg372-to-ter (R372X) substitution. The mutation was found by a combination of linkage analysis, whole-exome sequencing, and Sanger sequencing. Transfection of HEK293 cells with TMEM43 with the R372X mutation resulted in decreased TMEM43 protein content, possibly due to decreased protein stability. Mouse models that were heterozygous or homozygous for the R372X mutation in the TMEM43 gene demonstrated progressive hearing loss and abnormal passive conductance current from glia-like supporting cells in the organ of Corti of the inner ear.
Baskin, B., Skinner, J. R., Sanatani, S., Terespolsky, D., Krahn, A. D., Ray, P. N., Scherer, S. W., Hamilton, R. M. TMEM43 mutations associated with arrhythmogenic right ventricular cardiomyopathy in non-Newfoundland populations. Hum. Genet. 132: 1245-1252, 2013. [PubMed: 23812740] [Full Text: https://doi.org/10.1007/s00439-013-1323-2]
Bengtsson, L., Otto, H. LUMA interacts with emerin and influences its distribution at the inner nuclear membrane. J. Cell Sci. 121: 536-548, 2008. [PubMed: 18230648] [Full Text: https://doi.org/10.1242/jcs.019281]
Christensen, A. H., Andersen, C. B., Tybjaerg-Hansen, A., Haunso, S., Svendsen, J. H. Mutation analysis and evaluation of the cardiac localization of TMEM43 in arrhythmogenic right ventricular cardiomyopathy. Clin. Genet. 80: 256-264, 2011. [PubMed: 21214875] [Full Text: https://doi.org/10.1111/j.1399-0004.2011.01623.x]
Jang, M. W., Kim, T. Y., Sharma, K., Kwon, J., Yi, E., Lee, C. J. A deafness associated protein TMEM43 interacts with KCNK3 (TASK-1) two-pore domain K+ (K2P) channel in the cochlea. Exp. Neurobiol. 30: 319-328, 2021. [PubMed: 34737237] [Full Text: https://doi.org/10.5607/en21028]
Jang, M. W., Oh, D.-Y., Yi, E., Liu, X., Ling, J., Kim, N., Sharma, K., Kim, T. Y., Lee, S., Kim, A.-R., Kim, M. Y., Kim, M., and 32 others. A nonsense TMEM43 variant leads to disruption of connexin-linked function and autosomal dominant auditory neuropathy spectrum disorder. Proc. Nat. Acad. Sci. 118: e2019681118, 2021. [PubMed: 34050020] [Full Text: https://doi.org/10.1073/pnas.2019681118]
Liang, W. C., Mitsuhashi, H., Keduka, E., Nonaka, I., Noguchi, S., Nishino, I., Hayashi, Y. K. TMEM43 mutations in Emery-Dreifuss muscular dystrophy-related myopathy. Ann. Neurol. 69: 1005-1013, 2011. [PubMed: 21391237] [Full Text: https://doi.org/10.1002/ana.22338]
Merner, N. D., Hodgkinson, K. A., Haywood, A. F. M., Connors, S., French, V. M., Drenckhahn, J.-D., Kupprion, C., Ramadanova, K., Thierfelder, L., McKenna, W., Gallagher, B., Morris-Larkin, L., Bassett, A. S., Parfrey, P. S., Young, T.-L. Arrhythmogenic right ventricular cardiomyopathy type 5 is a fully penetrant, lethal arrhythmic disorder caused by a missense mutation in the TMEM43 gene. Am. J. Hum. Genet. 82: 809-821, 2008. [PubMed: 18313022] [Full Text: https://doi.org/10.1016/j.ajhg.2008.01.010]