<scp><i>MORC</i></scp><i>2</i> mutations cause axonal <scp>C</scp>harcot–<scp>M</scp>arie–<scp>T</scp>ooth disease with pyramidal signs

Albulym, Obaid; Kennerson, Marina; Harms, Matthew B.; Drew, Alexander P.; Siddell, Anna; Auer‐Grumbach, Michaela; Pestronk, Alan; Connolly, Anne M.; Baloh, Robert H.; Züchner, Stephan; Reddel, Stephen W.; Nicholson, Garth A.

doi:10.1002/ana.24575

Cited by 52 publications

(78 citation statements)

References 24 publications

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“…However, we recognized mental retardation in four patients, with two of them showing abnormalities on brain or spinal MRI. In fact, learning difficulties and brain abnormalities on MRI were reported in an Australian family . We identified, for the first time, spinal cord atrophy in a Japanese patient carrying a MORC2 variant.…”

Section: Discussionmentioning

confidence: 86%

Clinical and mutational spectrum of Charcot–Marie–Tooth disease type 2Z caused by MORC2 variants in Japan

Ando

Okamoto

Yoshimura

et al. 2017

Euro J of Neurology

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Section: Discussionmentioning

confidence: 86%

Clinical and mutational spectrum of Charcot–Marie–Tooth disease type 2Z caused by MORC2 variants in Japan

Ando

Okamoto

Yoshimura

et al. 2017

Euro J of Neurology

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“…6a)29–33. 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

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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.

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“…Intriguingly, many hits uncovered by our screen (e.g. FA factors, MORC2 and SETX) are associated with human disorders 13,14,15,16,17 .…”

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confidence: 88%

Selective silencing of euchromatic L1s revealed by genome-wide screens for L1 regulators

Liu

Lee

Swigut

et al. 2017

Nature

273

365

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Summary Transposable elements (TEs) are now recognized not only as parasitic DNA, whose spread in the genome must be controlled by the host, but also as major players in genome evolution and regulation1,2,3,4,5,6. Long INterspersed Element-1 (LINE-1 or L1), the only currently autonomous mobile transposon in humans, occupies 17% of the genome and continues to generate inter- and intra-individual genetic variation, in some cases resulting in disease1,2,3,4,5,6,7. Nonetheless, how L1 activity is controlled and what function L1s play in host gene regulation remain incompletely understood. Here, we use CRISPR/Cas9 screening strategies in two distinct human cell lines to provide the first genome-wide survey of genes involved in L1 retrotransposition control. We identified functionally diverse genes that either promote or restrict L1 retrotransposition. These genes, often associated with human diseases, control the L1 lifecycle at transcriptional or post-transcriptional levels and in a manner that can depend on the endogenous L1 sequence, underscoring the complexity of L1 regulation. We further investigated L1 restriction by MORC2 and human silencing hub (HUSH) complex subunits MPP8 and TASOR8. HUSH/MORC2 selectively bind evolutionarily young, full-length L1s located within transcriptionally permissive euchromatic environment, and promote H3K9me3 deposition for transcriptional silencing. Interestingly, these silencing events often occur within introns of transcriptionally active genes and lead to down-regulation of host gene expression in a HUSH/MORC2-dependent manner. Together, we provide a rich resource for studies of L1 retrotransposition, elucidate a novel L1 restriction pathway, and illustrate how epigenetic silencing of TEs rewires host gene expression programs.

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MORC2 mutations cause axonal Charcot–Marie–Tooth disease with pyramidal signs

Cited by 52 publications

References 24 publications

Clinical and mutational spectrum of Charcot–Marie–Tooth disease type 2Z caused by MORC2 variants in Japan

Clinical and mutational spectrum of Charcot–Marie–Tooth disease type 2Z caused by MORC2 variants in Japan

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

Selective silencing of euchromatic L1s revealed by genome-wide screens for L1 regulators

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