TMEM43
Details
TMEM43 encodes transmembrane protein 43 and was the first non-desmosomal gene identified to cause ARVC (2008). A single founder missense variant, p.Ser358Leu, is considered definitively pathogenic and is highly prevalent in Newfoundland, Canada, but observed worldwide. TMEM43-cardiomyopathy is one of the most malignant forms of ACM — nearly fully penetrant in males with a very high risk of ventricular arrhythmias and SCD, warranting early consideration of ICD implantation.
Key Facts
- Founder variant: p.Ser358Leu — a definitively pathogenic missense mutation. (sources/ACM-Genotype-Mx-JCE-2024, rating: high)
- Penetrance: Nearly fully penetrant in males. Highly malignant with very high risk of VA and SCD. (sources/ACM-Genotype-Mx-JCE-2024)
- ECG: Poor R-wave progression is more common than precordial T-wave inversions (distinctive feature vs other ACM forms). LV dilatation. (sources/ACM-Genotype-Mx-JCE-2024)
- Exercise: Associated with worse clinical outcomes — exercise restriction warranted. (sources/ACM-Genotype-Mx-JCE-2024)
- Management: Early ICD implantation indicated for at-risk male TMEM43 variant carriers. Should be regarded as a highly malignant disease. (sources/ACM-Genotype-Mx-JCE-2024)
- ICD survival benefit demonstrated: A study of p.S358L-TMEM43 carriers showed significantly better survival in those treated with ICD vs conventional non-ICD management — providing direct evidence for early ICD in this genotype. (sources/dcm-precision-hfreview-2022, rating: high)
- Sex-specific prognosis: Affected males were hospitalised 4× more often than affected females and died at younger ages. (sources/dcm-precision-hfreview-2022, rating: high)
- Prevalence: Great geographical differences — high in Newfoundland (founder effect); low elsewhere. (sources/ACM-Genotype-Mx-JCE-2024)
- Young men are at particularly high risk for severe arrhythmias. (sources/ACM-Genotype-Mx-JCE-2024)
Gene Therapy
- The haploinsufficiency question decides the strategy. TMEM43 truncating variants occur in the general population without disease, and TMEM43 haploinsufficient mice have only a mild phenotype — against a malignant course in p.S358L transgenic mice. So p.S358L behaves as a toxic gain rather than as simple loss, and the field is pursuing both directions: overexpressing wild-type TMEM43 and knocking down the mutant allele. (sources/gene-therapy-arrhythmia-cjca-2026, rating: high)
- Gene replacement works in mice, including after onset. Double-transgenic mice expressing wild-type human TMEM43 alongside p.S358L survived to a median 34.6 weeks versus 23.9, with better biventricular contractility, shorter P-wave and QRS durations, fewer PVCs, and less fibrosis with lower circulating fibrosis markers. AAV delivery of wild-type TMEM43 produced similar effects in neonates, and — importantly for human translation — given at 10 weeks, after phenotypic onset, it still improved lifespan and LVEF, though QRS duration did not change. (sources/gene-therapy-arrhythmia-cjca-2026)
- Transduction was only 10–30% of cardiomyocytes, which is a useful benchmark: the functional benefit was achieved at a fraction far below what structural repair would require, consistent with concepts/Gene-Therapy-Transduction-Threshold. (sources/gene-therapy-arrhythmia-cjca-2026)
- Allele-specific knockdown is the alternative and is feasible precisely because p.S358L accounts for an appreciable share of ACM cases worldwide, so a single construct would serve a large population — unlike the variant-by-variant problem in channelopathies.
Contradictions / Open Questions
- Data are dominated by the single p.Ser358Leu founder variant — whether other TMEM43 variants cause a similar phenotype is unclear.
- No TMEM43-specific risk calculator exists despite the distinctive natural history.
- Optimal ICD timing in female carriers is less well-defined than in males.
- Whether the near-complete male penetrance reflects biology or ascertainment bias in the Newfoundland founder population is debated.
Connections
- Related to entities/PKP2
- Related to entities/PLN
- Related to entities/DES
- Related to entities/ARVC
- Related to concepts/Arrhythmogenic-Cardiomyopathy
- Related to concepts/Exercise-Restriction-in-ARVC
- Related to sources/ACM-Genotype-Mx-JCE-2024
- Related to concepts/AAV-Gene-Delivery
- Related to concepts/Gene-Therapy-Transduction-Threshold