Dynamin 2 mutations in Charcot–Marie–Tooth neuropathy highlight the importance of clathrin-mediated endocytosis in myelination

Sidiropoulos, Paris; Miehe, Michaela; Bock, Thomas; Tinelli, Elisa; Oertli, Carole I.; Kuner, Rohini; Meijer, Dies; Wollscheid, Bernd; Niemann, Axel; Suter, Ueli

doi:10.1093/brain/aws061

Cited by 63 publications

(68 citation statements)

References 44 publications

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“…Our study along with several other reports emphasizes that DNM2 has a key role in endocytosis, and that disease-causing mutations impact on this function. 9,[21][22][23] We speculate that alterations in endocytosis during development could explain the pleiotropic phenotype observed in patients with this congenital syndrome. (d) The p.Phe379Val protein exhibits B20% lower GTPase activity using a malachite green-based assay (P-value *0.05 for three independent experiments using the Student's t-test).…”

Section: Discussionmentioning

confidence: 93%

Dynamin 2 homozygous mutation in humans with a lethal congenital syndrome

et al. 2012

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Heterozygous mutations in dynamin 2 (DNM2) have been linked to dominant Charcot-Marie-Tooth neuropathy and centronuclear myopathy. We report the first homozygous mutation in the DNM2 protein p.Phe379Val, in three consanguineous patients with a lethal congenital syndrome associating akinesia, joint contractures, hypotonia, skeletal abnormalities, and brain and retinal hemorrhages. In vitro membrane tubulation, trafficking and GTPase assays are consistent with an impact of the DNM2p.Phe379Val mutation on endocytosis. Although DNM2 has been previously implicated in axonal and muscle maintenance, the clinical manifestation in our patients taken together with our expression analysis profile during mouse embryogenesis and knockdown approaches in zebrafish resulting in defects in muscle organization and angiogenesis support a pleiotropic role for DNM2 during fetal development in vertebrates and humans.

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Section: Discussionmentioning

confidence: 93%

Dynamin 2 homozygous mutation in humans with a lethal congenital syndrome

et al. 2012

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“…PIPKIγ phosphorylates phosphatidylinositol 4-phosphate to generate phosphatidylinositol-4,5-bisphosphate (PIP 2 ) and the localized synthesis of PIP 2 is important for asymmetric process retraction during directional Schwann cell migration (Gatto et al, 2007). Dynamin 2 is involved in clathrin-mediated endocytosis and required for Schwann cell myelination (Sidiropoulos et al, 2012), CNTNAP1 is an essential component of Ranvier domains, while knockdown of ADCY6 orthologues in zebrafish blocked PNS myelination (Laquérriere et al, 2014). GLE1 function has not been associated with PNS myelination, however RNA expression profiling of spinal cord from LCCS1 fetuses indicated that oligodendrocyte dysfunction may be a factor in disease pathogenesis (Pakkasjarvi et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

Deficiency in the mRNA export mediator Gle1 impairs Schwann cell development in the zebrafish embryo

et al. 2016

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-GLE1 mutations cause lethal congenital contracture syndrome 1 (LCCS1), a severe autosomal recessive fetal motor neuron disease, and more recently have been associated with amyotrophic lateral sclerosis (ALS). The gene encodes a highly conserved protein with an essential role in mRNA export. The mechanism linking Gle1 function to motor neuron degeneration in humans has not been elucidated, but increasing evidence implicates abnormal RNA processing as a key event in the pathogenesis of several motor neuron

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“…The CMT-neuropathy related mutation G358R 16,17 is located in the C-terminus of L1N S (Extended Data Fig. 3c).…”

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confidence: 99%

Crystal structure of the dynamin tetramer

Reubold

Faelber

Plattner

et al. 2015

Nature

122

160

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The mechano-chemical protein dynamin is the prototype of the dynamin superfamily of large GTPases, which shape and remodel membranes in diverse cellular processes 1 .Dynamin forms predominantly tetramers in the cytosol, which oligomerize at the neck of clathrin-coated vesicles to mediate constriction and subsequent scission of the membrane 1 . Previous studies have described the architecture of dynamin dimers 2,3 , but the molecular determinants for dynamin assembly and its regulation have remained unclear. Here, we present the crystal structure of the nucleotide-free dynamin tetramer.Combining structural data with mutational studies, oligomerization measurements and molecular dynamics simulations, we suggest a mechanism of how oligomerization of dynamin is linked to the release of intramolecular auto-inhibitory interactions. We elucidate how mutations that interfere with tetramer formation and auto-inhibition can lead to the congenital diseases Charcot-Marie-Tooth neuropathy (CMT) 4 and centronuclear myopathy (CNM) 5 , respectively. Strikingly, the bent shape of the tetramer explains how dynamin assembles into a right-handed helical oligomer of defined diameter, which has direct implications for its function in membrane constriction.The three highly conserved vertebrate isoforms of dynamin contain five distinct domains (Extended Data Fig. 1a): an N-terminal GTPase (G) domain mediating nucleotide binding and hydrolysis, a bundle signaling element (BSE), a stalk, a pleckstrin homology (PH) domain involved in lipid binding, and a proline rich domain (PRD) mediating interaction with BAR-and SH3-domain containing scaffolding proteins 6 . To exert its function in clathrinmediated endocytosis (CME), dynamin assembles via the stalks into a helical array surrounding the necks of invaginating clathrin-coated pits (CCP) 7,8 . Dimerization of GTPbound G domains from neighboring helical rungs induces GTP hydrolysis 9 . The ensuing conformational changes are thought to be transmitted from the G domain via the BSE to the stalk resulting in a sliding motion of adjacent helix rungs, concomitant helix constriction 10 , and eventually membrane scission. The inherent tendency to form large assemblies at high protein concentrations has hampered crystallization of dynamin in the past. The use of non-3 oligomerizing mutants led to crystal structures of dynamin 1 2,3 . However, the postulated higher-order assembly interface was not resolved in these structures leaving the oligomerization mechanism unaddressed.We reasoned that an alternative assembly-affecting mutation, such as K361S in dynamin 3 11 , may disturb the oligomerization interface to a lesser extent than the previously used mutants. We obtained crystals of nucleotide-free dynamin 3-K361S lacking the PRD (dynamin 3(∆PRD)-K361S) that diffracted to 3.7 Å (Methods, Extended Data Fig. 1, Extended Data Table 1). Indeed, the asymmetric unit of the crystal lattice contained a dynamin tetramer that did not form the filamentous superstructures seen for dynamin 1 2,3 .The dynamin tetr...

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Dynamin 2 mutations in Charcot–Marie–Tooth neuropathy highlight the importance of clathrin-mediated endocytosis in myelination

Cited by 63 publications

References 44 publications

Dynamin 2 homozygous mutation in humans with a lethal congenital syndrome

Dynamin 2 homozygous mutation in humans with a lethal congenital syndrome

Deficiency in the mRNA export mediator Gle1 impairs Schwann cell development in the zebrafish embryo

Crystal structure of the dynamin tetramer

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