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LUMA in cardiac development and function.

LUMA (also known as TMEM43 or transmembrane protein 43) was best known for its association with arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D). ARVC/D is an inherited cardiomyopathy characterized by cardiomyocyte apoptosis, lethal ventricular tachycardia, and fibro-fatty infiltration mainly in the right ventricle (RV). More than 50% of patients with ARVC/D have mutations in genes of five component proteins of cardiac desmosomes, namely desmoplakin (DSP), plakophilin-2 (PKP2), desmoglein-2 (DSC2), desmocollin-2 (DSG2), and plakoglobin (JUP), which account for the major forms of ARVC (ARVC712). LUMA was initially identified as a nuclear envelope protein and later was shown to interact with the linker of nuclear and cytoskeleton (LINC) complex containing proteins SUN2, Emerin, Lamins A/C, and B1. However, immunostaining of LUMA at sarcolemmal membranes or at intercalated disks in human hearts had also been reported. A missense mutation of LUMA (S358L) was originally reported in 15 Canadian families suffering from ARVC5 with full penetrance. The association of this non-desmosomal genetic mutation with ARVC/D was further confirmed by additional ARVC/D patients in other European countries as well as the identification of additional missense mutations potentially associated with dilated cardiomyopathy. In addition, mutations in LUMA were found to be associated with Emery Dreifuss muscular dystrophy-related myopathy. Despite its close disease-association, the lack of a systematic evaluation of the physiological role of LUMA in cardiogenesis and postnatal heart function in vivo precluded a comprehensive understanding of its disease-causing mechanism or whether it is truly disease causing. The work by Stroud et al. published in this issue of Cardiovascular Research provided the first in vivo analysis of the potential patho-physiological roles of LUMA in cardiac function/development via the characterization of LUMA-null and LUMA(S358L) knock-in mice. Interestingly, the findings from this study suggested that mutations in LUMA alone might not be sufficient to cause ARVC/D. LUMA-null mice exhibited no detectable defects in cardiac formation and heart physiology, even up to 2 years of age. The study was carefully performed and documented convincingly with a series of morphological and functional analyses that LUMA was dispensable, or at least not a critical molecule, for normal cardiac physiology and development in mouse. In addition, mutant mice with LUMA deletions responded normally to b-adrenergic stimulation and to pressure overload induced by transverse aortic constriction. This phenotypical observation was further supported by the demonstration of normal expression levels and subcellular localizations of various LINC complex proteins, including Lamins A/C, B1, Sun1, Sun2, and Emerin. Clearly, the lack of LUMA in LINC complex did not cause malfunction or maladaptation of nuclear lamina/LINC complexes, mechano-transduction and transcriptional regulations as in the case of cardiomyopathy caused by lamin A/C mutations. Furthermore, it remains unclear if LUMA had a different expression pattern in mouse hearts vs. human hearts (see References 6 and 7 vs. Reference 9). Finally, the authors generated LUMA (S358L) knock-in mice. S358L mutant protein was found expressed and localized normally to the nuclear envelope. As seen in the LUMA-null mice, other LINC proteins were also unchanged in LUMA S358L mutant cardiac tissue. Again, this supposeddisease mimicking mouse model with LUMA(S358L) had normal cardiac function at baseline conditions when tested up to 12 months of age. Unfortunately, the levels of desmosomal proteins, especially plakoglobin (JUP) were not reported in this study. Downregulation of plakoglobin proteins in human ARVC/D hearts with LUMA mutations has been reported, which likely leads to the ARVC/D phenotypes. If desmosomal protein levels were not down regulated in these two mouse models, it may explain why these two mouse models with abnormal LUMA do not manifest ARVC/D phenotypes. What did we learn from this important, but largely negative study? As the authors pointed out, an unknown genetic modifier could be required to manifest an ARVC phenotype, which can be further validated by generating additional LUMA-mutant mice in different inbred mouse strains. It was also possible that the biochemical and physiological function of LUMA in human and mouse are different, which could lead to the certain discrepancies in pathogenic pathways by LUMA mutations between human and mouse. Using cardiomyocytes derived from patient-specific induced pluripotent stem cells will provide a vital way to determine its disease-causing mechanism and potential novel modifier genes/proteins. Of note, this study revealed that LUMA was found predominantly expressed in cardiac fibroblasts and coronary vascular smooth muscle cells, not as initially anticipated in cardiomyocytes in mouse hearts (but see reference 7 for LUMA locations in human hearts). This is also an important finding as it raises the possibility that the disease-causing LUMA (S358L) mutation functions in a cardiomyocyte non-autonomous