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

2017 ◽  
Author(s):  
Christopher H. Douse ◽  
Stuart Bloor ◽  
Yangci Liu ◽  
Maria Shamin ◽  
Iva A. Tchasovnikarova ◽  
...  
Keyword(s):  
Muscular Atrophy ◽  
Coiled Coil ◽  
Epigenetic Silencing ◽  
Missense Mutations ◽  
Wild Type ◽  
Dimer Interface ◽  
Charcot Marie Tooth Disease ◽  
Disease Mutations ◽  
Structural Mechanisms ◽  
Tooth Disease

AbstractMissense 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.

scholarly journals Complementation between mouse Mfn1 and Mfn2 protects mitochondrial fusion defects caused by CMT2A disease mutations

2007 ◽  
Vol 176 (4) ◽  
pp. 405-414 ◽  
Author(s):  
Scott A. Detmer ◽  
David C. Chan
Keyword(s):  
Axonal Degeneration ◽  
Mitochondrial Protein ◽  
Mitochondrial Fusion ◽  
Wild Type ◽  
Cell Type ◽  
Charcot Marie Tooth Disease ◽  
Disease Mutations ◽  
Cell Type Specific ◽  
In Trans ◽  
Tooth Disease

Mfn2, an oligomeric mitochondrial protein important for mitochondrial fusion, is mutated in Charcot-Marie-Tooth disease (CMT) type 2A, a peripheral neuropathy characterized by axonal degeneration. In addition to homooligomeric complexes, Mfn2 also associates with Mfn1, but the functional significance of such heterooligomeric complexes is unknown. Also unknown is why Mfn2 mutations in CMT2A lead to cell type–specific defects given the widespread expression of Mfn2. In this study, we show that homooligomeric complexes formed by many Mfn2 disease mutants are nonfunctional for mitochondrial fusion. However, wild-type Mfn1 complements mutant Mfn2 through the formation of heterooligomeric complexes, including complexes that form in trans between mitochondria. Wild-type Mfn2 cannot complement the disease alleles. Our results highlight the functional importance of Mfn1–Mfn2 heterooligomeric complexes and the close interplay between the two mitofusins in the control of mitochondrial fusion. Furthermore, they suggest that tissues with low Mfn1 expression are vulnerable in CMT2A and that methods to increase Mfn1 expression in the peripheral nervous system would benefit CMT2A patients.

Homozygous Expression of a Dominant Gene Causing Peroneal Muscular Atrophy (Charcot-Marie-Tooth Disease)

1974 ◽  
Vol 23 (S1) ◽  
pp. 217-220 ◽  
Author(s):  
H. Warner Kloepfer ◽  
James M. Killian
Keyword(s):  
Clinical Features ◽  
Nerve Conduction ◽  
Peripheral Nerves ◽  
Muscular Atrophy ◽  
Dominant Gene ◽  
Conduction Time ◽  
Charcot Marie Tooth ◽  
Charcot Marie Tooth Disease ◽  
Peroneal Muscular Atrophy ◽  
Tooth Disease

This study involves the presentation of a kindred from Southwestern Louisiana showing 66 individuals who were heterozygous for a rare dominant gene for a type of Charcot-Marie-Tooth disease with hypertrophy of peripheral nerves. Two marriages between heterozygotes resulted in the occurrence of five homozygous offsprings. Clinical features of these previously undescribed homozygotes are compared to the clinical features of the classic type of heterozygote. The value of using nerve-conduction time to detect the asymptomatic heterozygote for Charcot-Marie-Tooth disease is discussed.

scholarly journals Charcot-Marie-Tooth disease type 2S: Case report of a rare form associated with spinal muscular atrophy type IV

2021 ◽  
Vol 12 ◽  
pp. 1-6
Author(s):  
Marco Orsini ◽  
Acary Souza Bulle Oliveira ◽  
Antônio Marcos da Silva Catharino ◽  
Mauricio Sant’ Anna Junior ◽  
Felipe dos Santos Souza ◽  
...  
Keyword(s):  
Case Report ◽  
Spinal Muscular Atrophy ◽  
Muscular Atrophy ◽  
Disease Type ◽  
Rare Form ◽  
Charcot Marie Tooth ◽  
Spinal Muscular Atrophy Type ◽  
Charcot Marie Tooth Disease ◽  
Type Iv ◽  
Tooth Disease

scholarly journals Missense mutations in the SH3TC2 protein causing Charcot-Marie-Tooth disease type 4C affect its localization in the plasma membrane and endocytic pathway

2009 ◽  
Vol 18 (23) ◽  
pp. 4603-4614 ◽  
Author(s):  
Vincenzo Lupo ◽  
Máximo I. Galindo ◽  
Dolores Martínez-Rubio ◽  
Teresa Sevilla ◽  
Juan J. Vílchez ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Disease Type ◽  
Endocytic Pathway ◽  
Missense Mutations ◽  
Charcot Marie Tooth ◽  
Charcot Marie Tooth Disease ◽  
Tooth Disease

scholarly journals Truncating and Missense Mutations in IGHMBP2 Cause Charcot-Marie Tooth Disease Type 2

2014 ◽  
Vol 95 (5) ◽  
pp. 590-601 ◽  
Author(s):  
Ellen Cottenie ◽  
Andrzej Kochanski ◽  
Albena Jordanova ◽  
Boglarka Bansagi ◽  
Magdalena Zimon ◽  
...  
Keyword(s):  
Disease Type ◽  
Missense Mutations ◽  
Charcot Marie Tooth ◽  
Charcot Marie Tooth Disease ◽  
Tooth Disease

scholarly journals Connexin 32 mutations from X-linked Charcot-Marie-Tooth disease patients: functional defects and dominant negative effects.

1996 ◽  
Vol 7 (6) ◽  
pp. 907-916 ◽  
Author(s):  
Y Omori ◽  
M Mesnil ◽  
H Yamasaki
Keyword(s):  
Hela Cells ◽  
Dominant Negative ◽  
Dominant Negative Effect ◽  
Base Substitution ◽  
Cell Contact ◽  
Wild Type ◽  
Gap Junctional Intercellular Communication ◽  
Charcot Marie Tooth ◽  
Charcot Marie Tooth Disease ◽  
Tooth Disease

We have characterized the function of connexin (Cx) 32 gene mutations found in X-linked dominant Charcot-Marie-Tooth disease with respect to their ability to form functional gap junctions among themselves and to inactivate wild-type Cx32 by a dominant negative mechanism. We prepared four types of Cx32 mutant cDNAs and transfected them into HeLa cells, which do not show detectable levels of gap junctional intercellular communication (GJIC), nor expression of any connexins examined. Cells transfected with the wild-type Cx32 gene, but not those transfected with three different base substitution mutations (i.e. Cys 60 to Phe, Val 139 to Met, and Arg 215 to Trp), restored GJIC. Unexpectedly, in cells transfected with a nonsense mutant at codon 220, there was also restored GJIC. When we double-transfected these mutant constructs into the HeLa cells that had already been transfected with the wild-type Cx32 gene and thus were GJIC proficient, three base substitution mutants inhibited GJIC, suggesting that these three mutants can eliminate the function of wild-type Cx32 in a dominant negative manner. The nonsense mutation at codon 220 did not show such a dominant negative effect. Since both mutant and wild-type Cx32 mRNAs were detected, but only poor Cx32 protein expression at cell-cell contact areas was observed in the double transfectants, it is suggested that certain mutants form nonfunctional chimeric connexons with wild-type connexins, which are not properly inserted into the cytoplasmic membrane.

Report of a Patient with Multiple Mutations Leading to CharcotMarie-Tooth Disease and Distal Spinal Muscular Atrophy: A Case Report

2020 ◽  
Author(s):  
Atefeh MEHRABI ◽  
Dariush D. FARHUD ◽  
Karim NAYERNIA ◽  
Hossein SADIGHI ◽  
Marjan ZARIF-YEGANEH
Keyword(s):  
Spinal Muscular Atrophy ◽  
Muscular Atrophy ◽  
Lower Limbs ◽  
Charcot Marie Tooth ◽  
Charcot Marie Tooth Disease ◽  
Multiple Genes ◽  
First Case ◽  
Whole Exome ◽  
Different Types ◽  
Tooth Disease

The Charcot-Marie-Tooth disease is a group of progressive disorders that affects the peripheral nerves and results in loss of sensation and atrophy of muscles in lower limbs. There are several types of Charcot-Marie-Tooth and multiple genes are associated with this disease. Distal spinal muscular atrophy is an extremely rare disorder characterized by progressive pure lower motor neuron involvement. A 24 yr old woman using wheelchair referred to Farhud Genetic Clinic, Tehran, Iran in 2019, with progressive muscular atrophy, pain and Electromyography test suggesting Charcot-Marie-tooth. Both feet and hands were involved. Whole exome sequencing was performed on extracted DNA from her blood sample. We report the first case of a patient with different types of CharcotMarie-Tooth and distal spinal muscular atrophy simultaneously, which are as a result of mutations in multiple genes; this case is very uncommon.

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