MTM1 mutations in X-linked myotubular myopathy

Laporte, Jocelyn; Biancalana, Valérie; Tanner, Stephan M.; Kreß, Wolfram; Schneider, V.; Wallgren‐Pettersson, Carina; Herger, Franziska; Buj‐Bello, Anna; Blondeau, F; Liechti‐Gallati, Sabina; Mandel, Jean‐Louis

doi:10.1002/(sici)1098-1004(200005)15:5<393::aid-humu1>3.0.co;2-r

Cited by 215 publications

(162 citation statements)

References 48 publications

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“…The H31 cell line has a genomic deletion of the entire MTM1 (Laporte, Biancalana et al 2000;Laporte, Kress et al 2001) and the G92-628 cell line, referred to as XLCNM patient #2, has a stop mutation in MTM1 at amino acid 37 (Laporte, Biancalana et al 2000;Laporte, Kress et al 2001 …”

Section: Eukaryotic Cell Linesmentioning

confidence: 99%

A phosphoinositide conversion mechanism for exit from endosomes

Ketel¹,

Krauß²,

Nicot³

et al. 2016

Nature

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165

177

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I owe special thanks to Marnix Wieffer and Michael Krauß, who spent a lot of time helping me to get started in the lab, to overcome numerous experimental problem, I was not sure how to deal with, and frequently joined in discussions about my project with excellent advice. I am really grateful for your experimental support, Michael, and the time you invested in the project during our paper revision.Further, I would like to thank Jocelyn Laporte and his group, especially Anne-Sophie Nicot, at the IGBMC in Strasbourg for their support and a very fruitful collaboration, and Carsten Schultz and his group at the EMBL in Heidelberg for their support and constant supply with PIP/AMs. I owe special thanks to Dmytro Puchkov for the ultrastructural analysis and Eberhard Krause for mass spectrometry done within this project. I also need to acknowledge Markus Wenk and Federico Torta at the Singapore Lipidomics Incubator for joining the project at a very late stage, when we urgently needed help from lipidomics specialists. It was a pity that experiments did not work out as planned.I would further like to express my gratitude to two very skilled technicians in the AG Haucke lab: Silke Zillmann and Delia Löwe. Without your help it would have been impossible to achieve so much within the limited amount of time I had during the paper revision. by VPS34-IN1 treatment................................................... 52 2.3.11 Fluorescence microscopy................................................................................. 53 2.3.12 Flow cytometry............................................................................................ III SummaryPhosphoinositides (PIs) are a minor class of short-lived phospholipids that serve as crucial signposts of membrane identity. Thereby, PIs full fill important functions in cell signaling and membrane transport. PI 4-phosphates such as phosphatitylinositol-4-phosphate (PI(4)P) and phosphatitylinositol-4,5-bisphosphate (PI(4,5)P 2 ) are enriched at the plasma membrane (PM), on secretory organelles and lysosomes, while PI 3-phosphates, i.e.phosphatitylinositol-3-phosphate (PI(3)P), are a hallmark of the endosomal system.Directional transport between these compartments, thus, requires regulated PI conversion.However, PI conversion in exit from PI(3)P-enriched endosomes en route to the PI(4)P-and PI(4,5)P 2 -positive PM in endosomal recycling remained unknown.Here, we report that cargo exit from endosomes requires removal of PI(3)P by the PI(3)P 3-phosphatase myotubularin 1 (MTM1), and concomitant PI(4)P synthesis by PI 4-kinase type II α (PI4K2α). Loss of MTM1 causes endosomal accumulation of PI(3)P and PI(3)P effector proteins, i.e. sorting nexins, Kif16b-mediated outward traffic of PI(3)P containing endosomes and sub-plasmalemmal accumulation of exocytosis-deficient endosomes. As PI4K2α associates with MTM1 and thereby facilitates membrane recruitment of MTM1, these phenotypic changes are mimicked by loss of PI4K2α. The conversion of PI(3)P-to-PI(4)P is paralleled by a switch i...

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Section: Eukaryotic Cell Linesmentioning

confidence: 99%

A phosphoinositide conversion mechanism for exit from endosomes

Ketel¹,

Krauß²,

Nicot³

et al. 2016

Nature

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165

177

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“…We also engaged in this task because the scientific community has expressed the importance and the need for establishing a dedicated XLMTM database (mutational and clinical). 23 The implementation and curation of this LSDB followed guidelines reported elsewhere, 32,33 and is registered with the HGVS (LSDB list, http://www.hgvs.org/ dblist/glsdb.html).…”

Section: Mtm1-lovdmentioning

confidence: 99%

“…10,35 The largest proportion (93.3%) of pathogenic sequence variants described to date in MTM1 is that comprising small mutations. Since the last published MTM1 mutation update, 23 there has been a disproportional increase of missense and splicing mutations reported in MTM1. This might be attributed to the recent identification of additional XLMTM cases with a milder phenotype, often associated with these types of sequence variants.…”

Section: Database Content Analysismentioning

confidence: 99%

Expanding the MTM1 mutational spectrum: novel variants including the first multi-exonic duplication and development of a locus-specific database

Oliveira

Kreß

et al. 2012

Eur J Hum Genet

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Myotubular myopathy (MIM#310400), the X-linked form of Centronuclear myopathy (CNM) is mainly characterized by neonatal hypotonia and inability to maintain unassisted respiration. The MTM1 gene, responsible for this disease, encodes myotubularin -a lipidic phosphatase involved in vesicle trafficking regulation and maturation. Recently, it was shown that myotubularin interacts with desmin, being a major regulator of intermediate filaments. We report the development of a locus-specific database for MTM1 using the Leiden Open Variation database software (http://www.lovd.nl/MTM1), with data collated for 474 mutations identified in 472 patients (by June 2012). Among the entries are a total of 25 new mutations, including a large deletion encompassing introns 2-15. During database implementation it was noticed that no large duplications had been reported. We tested a group of eight uncharacterized CNM patients for this specific type of mutation, by multiple ligationdependent probe amplification (MLPA) analysis. A large duplication spanning exons 1-5 was identified in a boy with a mild phenotype, with results pointing toward possible somatic mosaicism. Further characterization revealed that this duplication causes an in-frame deletion at the mRNA level (r.343_444del). Results obtained with a next generation sequencing approach suggested that the duplication extends into the neighboring MAMLD1 gene and subsequent cDNA analysis detected the presence of a MTM1/MAMLD1 fusion transcript. A complex rearrangement involving the duplication of exon 10 has since been reported, with detection also enabled by MLPA analysis. It is thus conceivable that large duplications in MTM1 may account for a number of CNM cases that have remained genetically unresolved.

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“…2 Among the most severe myopathies, myotubular myopathy (also called X-linked centronuclear myopathy, XLMTM, OMIM #310400) is associated with neonatal hypotonia, muscle weakness and breathing difficulties in male patients and is due to loss-offunction mutations in the MTM1 gene. [3][4][5][6][7] Histopathological hallmarks comprise fiber hypotrophy and abnormal organelle positioning. 8 Different potential causes of the muscle weakness have been proposed for XLMTM, as triad structural defects, [9][10][11] unbalanced autophagy and protein homeostasis, [12][13][14] satellite cells alterations 15 or anomalies of the neuromuscular junction.…”

Section: Introductionmentioning

confidence: 99%

In vivo imaging of skeletal muscle in mice highlights muscle defects in a model of myotubular myopathy

et al. 2016

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Skeletal muscle structure and function are altered in different myopathies. However, the understanding of the molecular and cellular mechanisms mainly rely on in vitro and ex vivo investigations in mammalian models. In order to monitor in vivo the intracellular structure of the neuromuscular system in its environment under normal and pathological conditions, we set-up and validated non-invasive imaging of ear and leg muscles in mice. This original approach allows simultaneous imaging of different cellular and intracellular structures such as neuromuscular junctions and sarcomeres, reconstruction of the 3D architecture of the neuromuscular system, and video recording of dynamic events such as spontaneous muscle fiber contraction. Second harmonic generation was combined with vital dyes and fluorescentcoupled molecules. Skin pigmentation, although limiting, did not prevent intravital imaging. Using this versatile toolbox on the Mtm1 knockout mouse, a model for myotubular myopathy which is a severe congenital myopathy in human, we identified several hallmarks of the disease such as defects in fiber size and neuromuscular junction shape. Intravital imaging of the neuromuscular system paves the way for the follow-up of disease progression or/and disease amelioration upon therapeutic tests. It has also the potential to reduce the number of animals needed to reach scientific conclusions.

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MTM1 mutations in X-linked myotubular myopathy

Cited by 215 publications

References 48 publications

A phosphoinositide conversion mechanism for exit from endosomes

A phosphoinositide conversion mechanism for exit from endosomes

Expanding the MTM1 mutational spectrum: novel variants including the first multi-exonic duplication and development of a locus-specific database

In vivo imaging of skeletal muscle in mice highlights muscle defects in a model of myotubular myopathy

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