Dynamin 2 mutations cause sporadic centronuclear myopathy with neonatal onset

Bitoun, Marc; Bevilacqua, Jorge A.; Prudhon, Bernard; Maugenre, Svetlana; Taratuto, Ana Lía; Monges, Soledad; Lubieniecki, Fabiana; Cancés, Claude; Uro‐Coste, Emmanuelle; Mayer, M.; Fardeau, Michel; Romero, Norma B.; Guicheney, Pascale

doi:10.1002/ana.21235

Cited by 136 publications

(111 citation statements)

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“…Multiple missense mutations within the DNM2 gene have been linked to autosomal-dominant CNMs (7,8,27,28). Interestingly, these mutations are heterozygous missense mutations or small deletions that do not affect DNM2 transcript levels, protein expression, or localization (8,28).…”

Section: Discussionmentioning

confidence: 99%

“…Among the strongly predicted targets of miR-133a is Dnm2 mRNA, encoding a large GTPase implicated in endocytosis, membrane trafficking, and regulation of the actin and microtubule cytoskeletons (11). Point mutations in the human DNM2 gene, thought to act in a dominant-negative manner, cause the autosomal-dominant form of CNM (7,8,27,28). The 3′ UTR of Dnm2 mRNA contains an evolutionarily conserved miR-133a binding site ( Figure 5A).…”

Section: Figurementioning

confidence: 99%

“…The autosomal-dominant form of CNM is associated with a wide clinical spectrum of slowly progressive CNMs, from those beginning in childhood or adolescence to more severe sporadic forms with neonatal onset (7)(8)(9). Multiple missense mutations in the DNM2 locus have been identified in recent years, hence, the autosomal-dominant CNM is also called DNM2-associated CNM.…”

Section: Introductionmentioning

confidence: 99%

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Mice lacking microRNA 133a develop dynamin 2–dependent centronuclear myopathy

Liu¹,

Bezprozvannaya²,

Shelton³

et al. 2011

J. Clin. Invest.

143

146

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MicroRNAs modulate cellular phenotypes by inhibiting expression of mRNA targets. In this study, we have shown that the muscle-specific microRNAs miR-133a-1 and miR-133a-2 are essential for multiple facets of skeletal muscle function and homeostasis in mice. Mice with genetic deletions of miR-133a-1 and miR-133a-2 developed adult-onset centronuclear myopathy in type II (fast-twitch) myofibers, accompanied by impaired mitochondrial function, fast-to-slow myofiber conversion, and disarray of muscle triads (sites of excitation-contraction coupling). These abnormalities mimicked human centronuclear myopathies and could be ascribed, at least in part, to dysregulation of the miR-133a target mRNA that encodes dynamin 2, a GTPase implicated in human centronuclear myopathy. Our findings reveal an essential role for miR-133a in the maintenance of adult skeletal muscle structure, function, bioenergetics, and myofiber identity; they also identify a potential modulator of centronuclear myopathies.

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Section: Discussionmentioning

confidence: 99%

Section: Figurementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Mice lacking microRNA 133a develop dynamin 2–dependent centronuclear myopathy

Liu¹,

Bezprozvannaya²,

Shelton³

et al. 2011

J. Clin. Invest.

143

146

View full text Add to dashboard Cite

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“…14 DNM2: Thirteen heterozygous missense changes or in-frame deletions or insertions have been reported with hotspots at position 368, 369, 465, 522, 618 and 619. 5,[15][16][17][18][19][20] In the middle domain, the recurrent p.R465W mutation is most common, likely accounting for B25% of families, whereas p.E368K and p.R369W are found in B20% and B10% of families, respectively. The PH domain mutation p.R522H is found in roughly 10% of families, whereas mutations of residues 618 and 619 account for about 15% of families.…”

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confidence: 99%

Clinical utility gene card for: Centronuclear and myotubular myopathies

et al. 2012

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“…The DNM2 molecule consists of five functional domains: an N-terminal catalytic domain; a so-called "middle domain" implicated in dynamin-dynamin interactions; a PH domain involved in phosphoinositide binding; a GTPase effector domain, which interacts with the catalytic domain and stimulates its GTPase activity; and a C-terminal proline/arginine-rich domain, which mediates interactions of dynamin with other proteins. Most of the currently known CNM-associated dynamin mutations are located in the middle and PH domains (4,13), but others have recently been identified in the GTPase effector domain (3,14).…”

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confidence: 99%

Dynamin 2 Mutants Linked to Centronuclear Myopathies Form Abnormally Stable Polymers

Wang

Baryłko

Byers

et al. 2010

Journal of Biological Chemistry

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Mutations in the dynamin 2 gene have been identified in patients with autosomal dominant forms of centronuclear myopathy (CNM). Dynamin 2 is a ubiquitously expressed ϳ100-kDa GTPase that assembles around the necks of vesiculating membranes and promotes their constriction and scission. It has also been implicated in regulation of the actin and microtubule cytoskeletons. At present, the cellular functions of dynamin 2 that are affected by CNM-linked mutations are not well defined, and the effects of these mutations on the physical and enzymatic properties of dynamin have been not examined. Here, we report the expression, purification, and characterization of four CNMassociated dynamin mutants. All four mutants display higher than wild-type GTPase activities, and more importantly, the mutants form high order oligomers that are significantly more resistant than wild-type dynamin 2 to disassembly by guanine nucleotides or high ionic strength. These observations suggest that the corresponding wild-type residues serve to prevent excessive or prolonged dynamin assembly on cellular membranes or inappropriate self-assembly in the cytoplasm. To our knowledge, this report contains the first identification of point mutations that enhance the stability of dynamin polymers without impairing their ability to bind and/or hydrolyze GTP. We envision that the formation of abnormally large and stable complexes of these dynamin mutants in vivo contributes to their role in CNM pathogenesis. Autosomal dominant CNM2 is a congenital disorder that commonly results in muscle weakness and wasting, ptosis, and ophthalmoplegia (reviewed in Ref. 1). As the name implies, the most evident histopathological feature is the presence of a large number of muscle fibers of centrally (rather than peripherally) located nuclei. Other characteristics include a relative increase in the number of type I fibers, hypertrophy of these fibers, and the presence of sarcoplasmic strands distributed radially around the central nuclei. In 2005, Bitoun et al. (2) reported the identification of four mutations in the DNM2 (dynamin 2) gene in patients with autosomal dominant CNM, and an additional seven mutations have since been identified (3, 4). DNM2 is a ubiquitously expressed ϳ100-kDa GTPase that assembles into helical polymers around the necks of vesiculating membranes, thereby providing force for their constriction and scission (reviewed in Refs. 5-8). In addition to its well characterized roles in endocytosis and Golgi budding, DNM2 is also implicated in regulation of the actin (9, 10) and microtubule (11, 12) cytoskeletons. The DNM2 molecule consists of five functional domains: an N-terminal catalytic domain; a so-called "middle domain" implicated in dynamin-dynamin interactions; a PH domain involved in phosphoinositide binding; a GTPase effector domain, which interacts with the catalytic domain and stimulates its GTPase activity; and a C-terminal proline/arginine-rich domain, which mediates interactions of dynamin with other proteins. Most of the currently kn...

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Dynamin 2 mutations cause sporadic centronuclear myopathy with neonatal onset

Cited by 136 publications

References 10 publications

Mice lacking microRNA 133a develop dynamin 2–dependent centronuclear myopathy

Mice lacking microRNA 133a develop dynamin 2–dependent centronuclear myopathy

Clinical utility gene card for: Centronuclear and myotubular myopathies

Dynamin 2 Mutants Linked to Centronuclear Myopathies Form Abnormally Stable Polymers

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