Severe axonal Charcot-Marie-Tooth disease with proximal weakness caused by<i>de novo</i>mutation in the<i>MORC2</i>gene

Laššuthová, Petra; Brožková, Dana Šafka; Krůtová, Marcela; Mazanec, Radim; Züchner, Stephan; Gonzalez, Michael; Seeman, Pavel

doi:10.1093/brain/awv411

Cited by 31 publications

(33 citation statements)

References 4 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…We focused on understanding the functional impact of the most prevalent mutation, an arginine to tryptophan substitution at residue 252 (R252W or p.Arg252Trp in Uniprot: Q9Y6X9-1), which results in a severe axonal form of CMT230. This is the identical mutation to the reported R190W variant of MORC229,31,32, which refers to a putative alternative isoform of the protein (Uniprot: Q9Y6X9-2) that lacks 62 amino acids at the N-terminus.…”

Section: Resultsmentioning

confidence: 99%

Hyperactivation of HUSH complex function by Charcot–Marie–Tooth disease mutation in MORC2

Timms²,

et al. 2017

View full text Add to dashboard Cite

Dominant mutations in the MORC2 gene have recently been shown to cause axonal Charcot-Marie-Tooth (CMT) disease, but the cellular function of MORC2 is poorly understood. Here, through a genome-wide CRISPR/Cas9-mediated forward genetic screen, we identify MORC2 as an essential gene required for epigenetic silencing by the HUSH complex. HUSH recruits MORC2 to target sites in heterochromatin. We exploit a new method – Differential Viral Accessibility (DIVA) – to show that loss of MORC2 results in chromatin decompaction at these target loci, which is concomitant with a loss of H3K9me3 deposition and transcriptional derepression. The ATPase activity of MORC2 is critical for HUSH-mediated silencing, and the most common mutation affecting the ATPase domain found in CMT patients (R252W) hyper-activates HUSH-mediated repression in neuronal cells. These data define a critical role for MORC2 in epigenetic silencing by the HUSH complex and provide a mechanistic basis underpinning the role of MORC2 mutations in CMT disease.

show abstract

Section: Resultsmentioning

confidence: 99%

Hyperactivation of HUSH complex function by Charcot–Marie–Tooth disease mutation in MORC2

Timms²,

et al. 2017

View full text Add to dashboard Cite

show abstract

“…Kürzlich konnte das Gen MORC2, das für ein Zink-Finger-2-Protein kodiert, bei Familien, die an einer axonalen CMT2 leiden, identifiziert werden. Sporadische Fälle von CMT2 mit MORC2-Mutationen sind bereits aus Europa, Asien und Australien bekannt [18][19][20]. In 2 Familien mit autosomal-dominanter axonaler CMT2 wurde ein neuer Krankheitsmechanismus über Frameshift-Mutationen des Neurofilament-Schwerkettengens (NEFH) und Akkumulation toxischer Proteinaggregate [21,22] detektiert.…”

Section: Einführungunclassified

Aktuelles zur Charcot-Marie-Tooth-Erkrankung

Bartl¹,

Stassart²,

Fledrich³

et al. 2019

Nervenheilkunde

View full text Add to dashboard Cite

ZUSAMMENFASSUNGDie Charcot-Marie-Tooth-Erkrankung (CMT) ist die häufigste hereditäre Neuropathie (Prävalenz 1:2500) mit über 90 assoziierten Genen. Der häufigste Subtyp (CMT1A), assoziiert mit einer Duplikation des peripheren Myelinprotein-22-Gens (PMP22) ist Ursache für 40–50 % aller Fälle. Klinische Zeichen sind distal symmetrische Paresen, Atrophien, Sensibilitätsstörungen, Fußdeformitäten und Areflexie. Validierte Skalen zur Evaluation der Beeinträchtigung (CMTNS2, ONLS, 9-hole-pegtest, Gehtestungen) sind verfügbar und molekulare Biomarker aus Blut und Hautbiopsien wurden validiert. Therapieoptionen im Entwicklungsstadium sind das Gen-Silencing (Minderung der Überexpression von PMP22), Sekretasen zur Regulierung der Neuregulinaktivität mit Einfluss auf Meylindicke und Funktion sowie Inhibitoren des Kalziuminfluxes in Schwannzellen. PXT3003 (Sorbitol, Naltrexon, Baclofen) wurde im Tiermodell erfolgreich getestet. Ein möglicher Therapieansatz mittels Substitution des Fettmoleküls Lecithin konnte in CMT1A-Ratten die Muskelkraft und die Anzahl myelinisierter Axone erhöhen.

show abstract

“…4B). The latter interactions are especially notable since a number of recent studies have shown that the R252W mutation causes Charcot-Marie-Tooth (CMT) disease 15,16,19,20 . We recently demonstrated that this mutation causes hyperactivation of HUSH-dependent epigenetic silencing 4 , leading to enhanced and accelerated re-repression of the GFP reporter in our functional assay.…”

Section: The Cw Domain Has a Regulatory Role In The Hush Effector Actmentioning

confidence: 99%

“…5A). MORC2(1-603) bearing CMT mutation R252W 15,16,19,20 showed a small decrease in the rate of ATP hydrolysis. In contrast, SMA mutation T424R 18,21 increased ATPase activity approximately threefold.…”

Section: Disease Mutations Modulate the In Vitro And In Vivo Activitimentioning

confidence: 99%

See 1 more Smart Citation

Neuropathic mutations in MORC2 perturb GHKL ATPase dimerization dynamics and epigenetic silencing by multiple structural mechanisms

Douse

Bloor

et al. 2017

Preprint

View full text Add to dashboard Cite

Missense mutations in MORC2 cause neuropathies including spinal muscular atrophy and Charcot-Marie-Tooth disease. We recently identified MORC2 as an effector of epigenetic silencing by the HUSH complex. Here we report the biochemical and cellular activities of MORC2 variants, alongside crystal structures of wild-type and neuropathic forms of a human MORC2 fragment comprising the GHKL-type ATPase module and CW-type zinc finger. This fragment dimerizes upon binding ATP and contains a hinged, functionally critical coiled coil insertion absent in other GHKL ATPases. We find that dimerization and DNA binding of the MORC2 ATPase module transduce HUSH-dependent silencing. Disease mutations change the dynamics of dimerization by distinct structural mechanisms: destabilizing the ATPase-CW module, trapping the ATP lid or perturbing the dimer interface. These defects lead to modulation of HUSH function, thus providing a molecular basis for understanding MORC2-associated neuropathies.All rights reserved. No reuse allowed without permission.(which was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.

show abstract

Severe axonal Charcot-Marie-Tooth disease with proximal weakness caused byde novomutation in theMORC2gene

Cited by 31 publications

References 4 publications

Hyperactivation of HUSH complex function by Charcot–Marie–Tooth disease mutation in MORC2

Hyperactivation of HUSH complex function by Charcot–Marie–Tooth disease mutation in MORC2

Aktuelles zur Charcot-Marie-Tooth-Erkrankung

Neuropathic mutations in MORC2 perturb GHKL ATPase dimerization dynamics and epigenetic silencing by multiple structural mechanisms

Contact Info

Product

Resources

About