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Loss of Mtm1 causes cholestatic liver disease in a model of X-linked myotubular myopathy

ABSTRACT: Loss of Mtm1 causes cholestatic liver disease in a model of X-linked myotubular myopathy

PROVIDER: PRJNA986481 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR24992500_1.fastq.gz	Fastqsanger.gz
	SRR24992500_2.fastq.gz	Fastqsanger.gz
	SRR24992501_1.fastq.gz	Fastqsanger.gz
	SRR24992501_2.fastq.gz	Fastqsanger.gz
	SRR24992502_1.fastq.gz	Fastqsanger.gz

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Loss of Mtm1 causes cholestatic liver disease in a model of X-linked myotubular myopathy

Project description:X-linked myotubular myopathy (XLMTM) is a fatal congenital disorder caused by mutations in the MTM1 gene. Currently, there are no approved treatments, though AAV8-mediated gene transfer therapy has shown promise in animal models and preliminarily in patients. However, four patients with XLMTM treated with gene therapy have died from progressive liver failure, and hepatobiliary disease has now been recognized more broadly in association with XLMTM. In an attempt to understand whether loss of MTM1 itself is associated with liver pathology, we have characterized a novel liver phenotype in a zebrafish model of this disease. Specifically, we have found that loss-of-function mutations in mtm1 lead to severe liver abnormalities including impaired bile flux, structural abnormalities of the bile canaliculus, and improper endosomal-mediated trafficking of canalicular transporters. Using a reporter tagged Mtm1 zebrafish line, we have established localization of Mtm1 in the liver in association with Rab11 and canalicular transport proteins, and demonstrated that hepatocyte specific re-expression of Mtm1 can rescue the cholestatic phenotype. Lastly, we completed a targeted chemical screen, and found that Dynasore, a dynamin II inhibitor, is able to partially restore bile flow and transporter localization to the canalicular membrane. In summary, we demonstrate for the first time liver abnormalities that are directly caused by MTM1 mutation in a pre-clinical model, thus establishing the critical framework for better understanding and comprehensive treatment of the human disease.

2023-08-10 | GSE235571 | GEO

X-linked myotubular myopathy is associated with epigenetic alterations and is ameliorated by HDAC inhibition

Project description:X-linked myotubular myopathy (XLMTM) is a fatal neuromuscular disorder caused by loss of function mutations in MTM1 . At present, there are no directed therapies for XLMTM, and incomplete understanding of disease pathomechanisms. To address these knowledge gaps, we performed a drug screen in mtm1 mutant zebrafish andidentified four positive hits, including valproic acid, which functions as a potent suppressor of the mtm1 zebrafish phenotype via HDAC inhibition. We translated these findings to a mouse XLMTM model, and showed that valproic acid ameliorates the murine phenotype.

2022-08-08 | GSE210642 | GEO

Natural history of a mouse model of X-linked myotubular myopathy

Project description:Natural history of a mouse model of X-linked myotubular myopathy

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Natural history of a mouse model of X-linked myotubular myopathy

Project description:X-linked myotubular myopathy (XLMTM) is a severe monogenetic disorder of the skeletal muscle. It is caused by loss-of-expression/function mutations in the myotubularin (MTM1) gene. Much of what is known about the disease, as well as the treatment strategies, has been uncovered through experimentation in pre-clinical models, particularly the Mtm1 gene knockout mouse line (Mtm1 KO). Despite this understanding, and the identification of potential therapies, much remains to be understood about XLMTM disease pathomechanisms, and about the normal functions of MTM1 in muscle development. To lay the groundwork for addressing these knowledge gaps, we performed a natural history study of Mtm1 KO mice. This included longitudinal comparative analyses of motor phenotype, transcriptome and proteome profiles, muscle structure and targeted molecular pathways.We identified age-associated changes in gene expression, mitochondrial function, myofiber size and key molecular markers, including DNM2. Importantly, some molecular and histopathologic changes preceded overt phenotypic changes, while others, such as triad structural alternations, occurred coincidentally with the presence of severe weakness. In total, this study provides a comprehensive longitudinal evaluation of the murine XLMTM disease process, and thus provides a critical framework for future investigations.

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X-linked myotubular myopathy is associated with epigenetic alterations and is ameliorated by HDAC inhibition

Project description:X-linked myotubular myopathy is associated with epigenetic alterations and is ameliorated by HDAC inhibition

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Tamoxifen therapy in a murine model of myotubular myopathy (TAM4MTM)

Project description:Tamoxifen therapy in a murine model of myotubular myopathy (TAM4MTM)

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Tamoxifen treatment as a therapeutic approach in a murine model of X-linked myotubular myopathy (Mtm1-/y)

Project description:Tamoxifen treatment as a therapeutic approach in a murine model of X-linked myotubular myopathy (Mtm1-/y)

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Project description:Genetic downregulation of Dnm2 as a therapeutic approach in a murine model of X-linked myotubular myopathy (Mtm1-/y)

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Genetic surexpression of human BIN1 as a therapeutic approach in a murine model of X-linked myotubular myopathy (Mtm1-/y)

Project description:Genetic surexpression of human BIN1 as a therapeutic approach in a murine model of X-linked myotubular myopathy (Mtm1-/y)

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A mutation in MTM1 causes X-Linked myotubular myopathy in Boykin spaniels.

Project description:The purpose of this study was to report the findings of clinical and genetic evaluation of a 3-month old male Boykin spaniel (the proband) that presented with progressive weakness. The puppy underwent a physical and neurological examination, serum biochemistry and complete blood cell count, electrophysiological testing, muscle biopsy and whole genome sequencing. Clinical evaluation revealed generalized neuromuscular weakness with tetraparesis and difficulty holding the head up and a dropped jaw. There was diffuse spontaneous activity on electromyography, most severe in the cervical musculature. Nerve conduction studies were normal, the findings were interpreted as consistent with a myopathy. Skeletal muscle was grossly abnormal on biopsy and there were necklace fibers and abnormal triad structure localization on histopathology, consistent with myotubular myopathy. Whole genome sequencing revealed a premature stop codon in exon 13 of MTM1 (ChrX: 118,903,496 C > T, c.1467C>T, p.Arg512X). The puppy was humanely euthanized at 5 months of age. The puppy's dam was heterozygous for the variant, and 3 male puppies from a subsequent litter all of which died by 2 weeks of age were hemizygous for the variant. This naturally occurring mutation in Boykin spaniels causes a severe form of X-linked myotubular myopathy, comparable to the human counterpart.

| S-EPMC7532942 | biostudies-literature

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