{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nTMEM43, also known as LUMA, is an evolutionarily conserved integral membrane protein that displays a distinctive structure of four transmembrane domains and a prominent hydrophilic loop exposed to the perinuclear space. This unique topology underlies its preferential localization to the inner nuclear membrane, where it interacts directly with both A‐ and B‐type lamins and with emerin. Such associations point to a role as a tetraspanin‐like membrane organizer that is essential for maintaining nuclear envelope integrity. In addition, studies have shown that proper targeting of TMEM43 depends on its transmembrane segments that even promote homooligomerization, while post‐translational modifications—for example, N‐linked glycosylation—can alter its cellular distribution, with mislocalization implicated in disease states. Furthermore, TMEM43 has been found to participate in growth factor signaling; in response to EGF stimulation, it is recruited into a complex with scaffold proteins that mediates NF‑κB activation and influences cell survival and tumor progression."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "5"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn the cardiovascular realm, TMEM43 has been closely linked to a severe, autosomal dominant form of arrhythmogenic cardiomyopathy. A recurrent missense mutation (p.S358L) is responsible for a distinct subtype of arrhythmogenic right ventricular cardiomyopathy (ARVC) that is characterized by progressive fibrofatty replacement of myocardial tissue, conduction abnormalities, and an increased risk of sudden cardiac death. The impaired function of mutant TMEM43 is suggested to involve an altered response to adipogenic signals—for example, via a response element for PPARγ—and disruption of intercalated disc protein complexes, which are crucial for proper electrical conduction in cardiomyocytes. Consistent findings across multiple clinical and genetic studies—including observations of altered subcellular localization, reduced immunoreactive signal for desmosomal components like plakoglobin, and conduction slowing—underscore its central role in the pathogenesis of ARVC. In several cohorts spanning diverse populations, genetic screening for TMEM43 variants has proven invaluable in risk stratification and clinical management of affected families, with additional findings revealing a common ancestral haplotype among carriers."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "6", "end_ref": "19"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its well‐established role in cardiomyopathy, TMEM43 has also emerged as a player in other pathophysiological contexts. Notably, in cochlear glia‐like supporting cells, TMEM43 modulates the function of gap junction channels by interacting with key connexins (Cx26 and Cx30); mutations in the gene have been linked to an auditory neuropathy spectrum disorder marked by impaired speech discrimination despite preserved sound sensitivity. These findings extend the functional repertoire of TMEM43 from maintaining nuclear and intercellular integrity in muscle to impacting cellular communication in the inner ear."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "20"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Luiza Bengtsson, Henning Otto "}, {"type": "b", "children": [{"type": "t", "text": "LUMA interacts with emerin and influences its distribution at the inner nuclear membrane."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Cell Sci (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1242/jcs.019281"}], "href": "https://doi.org/10.1242/jcs.019281"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18230648"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18230648"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Wen-Chen Liang, Hiroaki Mitsuhashi, Etsuko Keduka, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "TMEM43/LUMA is a key signaling component mediating EGFR-induced NF-κB activation and tumor progression."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Oncogene (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/onc.2016.430"}], "href": "https://doi.org/10.1038/onc.2016.430"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27991920"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27991920"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Haruki Shinomiya, Hisakazu Kato, Yuki Kuramoto, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Aberrant accumulation of TMEM43 accompanied by perturbed transmural gene expression in arrhythmogenic cardiomyopathy."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "FASEB J (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1096/fj.202100800R"}], "href": "https://doi.org/10.1096/fj.202100800R"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "34674311"}], "href": "https://pubmed.ncbi.nlm.nih.gov/34674311"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Miriam Zink, Anne Seewald, Mareike Rohrbach, et al. 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