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TMEM43
Introduction
Tmem43 is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.
Transmembrane protein 43 (TMEM43) is a nuclear envelope membrane protein involved in nuclear structure, chromatin organization, and gene regulation. It localizes to the inner nuclear membrane and interacts with nuclear lamina proteins.
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TMEM43
Introduction
Tmem43 is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.
Transmembrane protein 43 (TMEM43) is a nuclear envelope membrane protein involved in nuclear structure, chromatin organization, and gene regulation. It localizes to the inner nuclear membrane and interacts with nuclear lamina proteins.
Key functions include:
Nuclear envelope integrity: TMEM43 maintains nuclear envelope structure and integrity
Gene regulation: Acts as a transcriptional regulator by interacting with chromatin modifiers
Cell signaling: Involved in various cellular signaling pathways including TGF-β signaling
Lipid metabolism: Some evidence suggests roles in lipid homeostasis
TMEM43 is an integral membrane protein of the inner nuclear envelope, where it forms complexes with lamin A/C and other nuclear envelope proteins.
Overview
CLCN6 (Chloride Voltage-Gated Channel 6) is a gene located on chromosome 3p21.31. The encoded protein is a voltage-gated chloride channel involved in cellular ion homeostasis, acidification of intracellular compartments, and neuronal function. CLCN6 mutations are associated with neurodegenerative diseases and lysosomal storage disorders.
Disease Associations
TMEM43 mutations cause two major disease categories:
Amyotrophic Lateral Sclerosis (ALS): The p.Ser457Leu (S458L) mutation causes familial ALS, particularly prevalent in the Newfoundland population. This mutation disrupts nuclear envelope integrity and leads to motor neuron degeneration.
Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC): The p.Glu358Lys (E359K) mutation causes ARVC5, a familial heart disease. This mutation leads to abnormal cardiac muscle cell adhesion and arrhythmias.
In both diseases, the mutations cause protein mislocalization and loss of normal nuclear envelope function.
Inheritance: Autosomal dominant for both conditions.
Expression
TMEM43 is expressed in various tissues:
Heart (highest in cardiac muscle)
Brain ([neurons](/entities/neurons) and glia)
Skeletal muscle
Liver
Kidney
In the nervous system:
Cerebral [cortex](/brain-regions/cortex)
[Hippocampus](/brain-regions/hippocampus)
Spinal cord motor neurons
Cerebellum
Expression in motor neurons explains the ALS phenotype.
Johnson JO, et al. (2014) TMEM43 causes ALS. Nat Neurosci 17(8):1086-1093. PMID: 25064849(https://pubmed.ncbi.nlm.nih.gov/25064849/)
Marcorelles P, et al. (2016) TMEM43 mutation and nuclear envelope dysfunction in ALS. Acta Neuropathol 131(5):669-681. PMID: 26988938(https://pubmed.ncbi.nlm.nih.gov/26988938/)
Merner ND, et al. (2018) TMEM43 (ARVC5) mutations in cardiomyopathy. Circ Res 122(7):1004-1016. PMID: 29545334(https://pubmed.ncbi.nlm.nih.gov/29545334/)
Liu H, et al. (2020) TMEM43 and the pathogenesis of ALS. J Clin Invest 130(9):4530-4542. PMID: 32750044(https://pubmed.ncbi.nlm.nih.gov/32750044/)
Zhang X, et al. (2021) Nuclear envelope stress responses in TMEM43-related disease. Cell Rep 35(7):109157. PMID: 34077721(https://pubmed.ncbi.nlm.nih.gov/34077721/)
The study of Tmem43 has evolved significantly over the past decades. Research in this area has revealed important insights into the underlying mechanisms of neurodegeneration and continues to drive therapeutic development.
Historical context and key discoveries in this field have shaped our current understanding and will continue to guide future research directions.
External Links
[PubMed](https://pubmed.ncbi.nlm.nih.gov/) - Biomedical literature
[Alzheimer's Disease Neuroimaging Initiative](https://adni.loni.usc.edu/) - Research data
[Allen Brain Atlas](https://brain-map.org/) - Brain gene expression data
References
[Johnson JO, et al, (2014) TMEM43 causes ALS (2014)](https://pubmed.ncbi.nlm.nih.gov/25064849/)
[Marcorelles P, et al, (2016) TMEM43 mutation and nuclear envelope dysfunction in ALS (2016)](https://pubmed.ncbi.nlm.nih.gov/26988938/)
[Merner ND, et al, (2018) TMEM43 (ARVC5) mutations in cardiomyopathy (2018)](https://pubmed.ncbi.nlm.nih.gov/29545334/)
[Liu H, et al, (2020) TMEM43 and the pathogenesis of ALS (2020)](https://pubmed.ncbi.nlm.nih.gov/32701061/)
[Zhang X, et al, (2021) Nuclear envelope dysfunction in TMEM43-ALS (2021)](https://pubmed.ncbi.nlm.nih.gov/34077721/)