Isoform-specific mutation in Dystonin-b gene causes late-onset protein aggregate myopathy and cardiomyopathy

Yoshioka, N.; Kurose, M.; Yano, M.; Tran, D. M.; Okuda, S.; Mori-Ochiai, Y.; Horie, M.; Nagai, T.; Nishino, I.; Shibata, S.; Takebayashi, H.

doi:10.1101/2022.03.17.484743

bioRxiv · 10.1101/2022.03.17.484743

Isoform-specific mutation in Dystonin-b gene causes late-onset protein aggregate myopathy and cardiomyopathy

Yoshioka, N.·Kurose, M.·Yano, M.·Tran, D. M.·Okuda, S.·Mori-Ochiai, Y.·Horie, M.·Nagai, T.·Nishino, I.·Shibata, S.·Takebayashi, H.

View original source ↗Export metadata ↓

Abstract

Dystonin (DST), which encodes cytoskeletal linker proteins, express three tissue-selective isoforms: neural DST-a, muscular DST-b, and epithelial DST-e. DST mutations cause different disorders including hereditary sensory and autonomic neuropathy 6 (HSAN-VI) and epidermolysis bullosa simplex; however, etiology of the muscle phenotype in DST-related diseases has been unclear. Because DST-b contains all of the DST-a-encoding exons, known HSAN-VI mutations could affect both DST-a and DST-b isoforms. To investigate the specific function of DST-b in striated muscles, we generated a Dst-b-specific mutant mouse model harboring a nonsense mutation. Dst-b mutant mice exhibited late-onset protein aggregate myopathy and cardiomyopathy without neuropathy. We observed desmin aggregation, focal myofibrillar dissolution, and mitochondrial accumulation in striated muscles, which are common characteristics of myofibrillar myopathy. We also found nuclear inclusions containing p62, ubiquitin, and SUMO proteins with nuclear envelope invaginations as a unique pathological hallmark in Dst-b mutation-induced cardiomyopathy. RNA sequencing analysis revealed changes in expression of genes responsible for cardiovascular functions. In silico analysis identified DST-b alleles with nonsense mutations in populations worldwide, suggesting that some unidentified hereditary myopathy and cardiomyopathy are caused by DST-b mutations. Here, we demonstrate that the Dst-b isoform is essential for long-term maintenance of striated muscles.

Source connections

Published article ↗

Explore related subjects

pathology Preprint

Keep this discovery

Explore connections, maps & timelines

BibTeX RIS

Yoshioka, N., Kurose, M., Yano, M., Tran, D. M., Okuda, S., Mori-Ochiai, Y., Horie, M., Nagai, T., Nishino, I., Shibata, S., Takebayashi, H.. 2022-03-19. Isoform-specific mutation in Dystonin-b gene causes late-onset protein aggregate myopathy and cardiomyopathy. https://doi.org/10.1101/2022.03.17.484743

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

NAE1-Dependent Protein Neddylation Preserves Endothelial Identity and Vascular Integrity

Background: Endothelial dysfunction is a central driver of cardiovascular and inflammatory diseases, yet the post-translational mechanisms that preserve endothelial homeostasis remain incompletely understood. Protein neddylation, the covalent conjugation of a ubiquitin-like modifier, regulates diverse cellular processes, yet its physiological role in the vascular endothelium remains unknown. This study investigated whether protein neddylation is required to preserve endothelial identity and vascular homeostasis. Methods: We generated tamoxifen-inducible endothelial-specific Nae1 knockout mice to inhibit neddylation and combined bulk RNA sequencing, single-cell and single-nucleus transcriptomics, quantitative proteomics, biochemical analyses, and gain- and loss-of-function approaches to define the role of endothelial neddylation in vascular homeostasis and inflammatory injury. Results: Endothelial-specific Nae1 deletion caused rapid mortality associated with vascular leakage, platelet accumulation, inflammation, and multi-organ injury. Multi-omics analyses demonstrated profound loss of endothelial identity, characterized by suppression of core endothelial programs and activation of inflammatory, procoagulant, and pyroptotic pathways. Single-cell analyses revealed progressive endothelial dysfunction culminating in depletion of the endothelial population and remodeling of the vascular niche. Mechanistically, endothelial neddylation deficiency activated gasdermin D (GSDMD)- and gasdermin E (GSDME)-dependent pyroptosis, whereas dual inhibition of GSDMD and GSDME markedly attenuated inflammatory transcriptomic remodeling, vascular injury, hepatocyte death, immune cell infiltration, and platelet accumulation. Translational analyses demonstrated reduced endothelial neddylation in experimental endotoxemia and decreased expression of neddylation pathway components in human atherosclerosis and COVID-19 datasets. Conversely, restoration of endothelial neddylation partially reversed inflammatory endothelial transcriptomic reprogramming in vivo. Conclusions: NAE1-dependent protein neddylation is an essential regulator of endothelial identity and vascular integrity. Loss of endothelial neddylation promotes gasdermin-dependent pyroptosis and thrombo-inflammatory vascular injury, whereas restoration of the neddylation pathway mitigates inflammatory endothelial dysfunction. These findings identify endothelial neddylation as a fundamental mechanism maintaining vascular homeostasis and a potential therapeutic target for cardiovascular and inflammatory diseases.

pathology↗

bioRxiv2025

Novel cytometry-based characterization of lysosomal storage disease affected patient's cells

Wolman disease (WD) is a severe lysosomal storage disorder characterized by fatal lipid accumulation caused by the deficiency of a lipid metabolic enzyme, Lysosomal Acid Lipase (LAL), involved in the lysosomal hydrolysis of cholesterols and triglycerides. Due to the imbalance of lipids homeostasis, WD patients suffer from severe hepatosplenomegaly, hepatic failure and adrenal calcification resulting in a premature infant death within the first year of age. In this work, we explored multiple imaging analyses to fully characterize the phenotype of LAL deficient cells. In particular, we stained WD patients fibroblasts for intracellular lipid droplets (LD) and lysosomes and we analysed staining intensity and granularity as well as an increased number of LD and lysosomes using fluorescence wide field microscopy, confocal microscopy, conventional and image flow cytometry. Noteworthy, we showed that lipid homeostasis was restored upon delivery of a functional LAL transgene. Finally, since fibroblasts cannot be used as routine clinical test as they are difficult to collect from WD patients, we confirmed our observations in LAL deficient human blood cell lines and in peripheral blood mononuclear cells (PBMC) from LAL deficient (LAL-D) mouse model, as a proxy for easily accessible WD PBMC. Overall, we expect that this novel imaging analysis pipeline will help to diagnose WD, follow its progression and evaluate the success of enzyme replacement therapy or gene correction strategies for WD as well as other lysosomal storage disorders.

pathology↗

bioRxiv2025

Understanding wood decay diseases in western redcedar through development of ITS-sequencing and qPCR assays

Root and butt rot diseases cause high rates of wood decay in living stands of western redcedar (WRC; Thuja plicata Donn), one of the most valuable forest species in western North America. However, WRC susceptibility and the virulence of wood-decay-causing fungal pathogens are understudied, presenting a high risk for the WRC forest industry. To evaluate susceptibility of WRC to root and butt rot diseases and decay incidence, four pathogenic fungi, including Armillaria ostoyae, Coniferiporia weirii, Heterobasidion occidentale, and Perenniporia subacida, were used to inoculate WRC seedlings using two artificial methods. Next-generation sequencing (NGS) of internal transcribed spacer (ITS) region of the nuclear ribosomal DNA (rDNA) and quantitative polymerase chain reaction (qPCR) assays were developed to evaluate successful infection through detection of targeted pathogens inside the WRC tissues while development of disease was assessed by visual observation of wood decay. Disease incidence rates ranged from 20% to 60% while infection rates ranged from 80% to 100%, validating the effectiveness of the inoculation protocols. The qPCR assays designed with species-specific primers were validated for quantification of absolute abundance of C. weirii inside WRC host tissues with high sensitivity and specificity. These newly developed qPCR assays provide rapid, cost-effective, and accurate tools to detect early infection and latent infection in asymptomatic trees, with wide potential applications for surveillance of C. weirii-caused wood decay disease in greenhouse and field studies, as well as for screening of disease resistance in WRC breeding.

pathology↗