Mutations in the MORC2 gene cause axonal Charcot-Marie-Tooth disease
Por:
T. SEVILLA, V. LUPO, D. MARTINEZ-RUBIO, P. SANCHO, R. SIVERA, M. CHUMILLAS, M. GARCIA-ROMERO, S. PASCUAL-PASCUAL, N. MUELAS, J. DOPAZO, J. VILCHEZ, F. PALAU and Carmen Espinós
Publicada:
1 ene 2016
Resumen:
Charcot-Marie-Tooth disease (CMT) is a complex disorder with wide genetic heterogeneity. Here we present a new axonal Charcot-Marie-Tooth disease form, associated with the gene microrchidia family CW-type zinc finger 2 (MORC2). Whole-exome sequencing in a family with autosomal dominant segregation identified the novel MORC2 p. R190W change in four patients. Further mutational screening in our axonal Charcot-Marie-Tooth disease clinical series detected two additional sporadic cases, one patient who also carried the same MORC2 p. R190W mutation and another patient that harboured a MORC2 p. S25L mutation. Genetic and in silico studies strongly supported the pathogenicity of these sequence variants. The phenotype was variable and included patients with congenital or infantile onset, as well as others whose symptoms started in the second decade. The patients with early onset developed a spinal muscular atrophy-like picture, whereas in the later onset cases, the initial symptoms were cramps, distal weakness and sensory impairment. Weakness and atrophy progressed in a random and asymmetric fashion and involved limb girdle muscles, leading to a severe incapacity in adulthood. Sensory loss was always prominent and proportional to disease severity. Electrophysiological studies were consistent with an asymmetric axonal motor and sensory neuropathy, while fasciculations and myokymia were recorded rather frequently by needle electromyography. Sural nerve biopsy revealed pronounced multifocal depletion of myelinated fibres with some regenerative clusters and occasional small onion bulbs. Morc2 is expressed in both axons and Schwann cells of mouse peripheral nerve. Different roles in biological processes have been described for MORC2. As the silencing of Charcot-Marie-Tooth disease genes have been associated with DNA damage response, it is tempting to speculate that a deregulation of this pathway may be linked to the axonal degeneration observed in MORC2 neuropathy, thus adding a new pathogenic mechanism to the long list of causes of Charcot-Marie-Tooth disease.
Filiaciones:
T. SEVILLA:
Hosp Univ & Politecn La Fe, Dept Neurol, Avd Fernando Abril Martorell 106, Valencia 46026, Spain
Ctr Invest Biomed Red Enfermedades Raras CIBERER, C Eduardo Primo Yufera 13, Valencia 46012, Spain
Univ Valencia, Dept Med, Avd Blasco Ibanez 15, Valencia, Spain
:
Ctr Invest Biomed Red Enfermedades Raras CIBERER, C Eduardo Primo Yufera 13, Valencia 46012, Spain
CIPF, Program Rare & Genet Dis, C Eduardo Primo Yufera 13, Valencia 46012, Spain
CIPF, IBV CSIC Associated Unit, C Eduardo Primo Yufera 13, Valencia 46012, Spain
:
Ctr Invest Biomed Red Enfermedades Raras CIBERER, C Eduardo Primo Yufera 13, Valencia 46012, Spain
CIPF, Program Rare & Genet Dis, C Eduardo Primo Yufera 13, Valencia 46012, Spain
CIPF, IBV CSIC Associated Unit, C Eduardo Primo Yufera 13, Valencia 46012, Spain
:
Ctr Invest Biomed Red Enfermedades Raras CIBERER, C Eduardo Primo Yufera 13, Valencia 46012, Spain
CIPF, Program Rare & Genet Dis, C Eduardo Primo Yufera 13, Valencia 46012, Spain
CIPF, IBV CSIC Associated Unit, C Eduardo Primo Yufera 13, Valencia 46012, Spain
R. SIVERA:
Hosp Univ & Politecn La Fe, Dept Neurol, Avd Fernando Abril Martorell 106, Valencia 46026, Spain
M. CHUMILLAS:
Ctr Invest Biomed Red Enfermedades Raras CIBERER, C Eduardo Primo Yufera 13, Valencia 46012, Spain
Hosp Univ & Politecn La Fe, Dept Clin Neurophysiol, Avd Fernando Abril Martorell 106, Valencia 46026, Spain
M. GARCIA-ROMERO:
Hosp Univ La Paz, Dept Neuropaediat, P Castellana 261, Madrid 08046, Spain
S. PASCUAL-PASCUAL:
Hosp Univ La Paz, Dept Neuropaediat, P Castellana 261, Madrid 08046, Spain
N. MUELAS:
Hosp Univ & Politecn La Fe, Dept Neurol, Avd Fernando Abril Martorell 106, Valencia 46026, Spain
Ctr Invest Biomed Red Enfermedades Raras CIBERER, C Eduardo Primo Yufera 13, Valencia 46012, Spain
:
Ctr Invest Biomed Red Enfermedades Raras CIBERER, C Eduardo Primo Yufera 13, Valencia 46012, Spain
CIPF, Program Computat Genom, C Eduardo Primo Yufera 13, Valencia 46012, Spain
J. VILCHEZ:
Hosp Univ & Politecn La Fe, Dept Neurol, Avd Fernando Abril Martorell 106, Valencia 46026, Spain
Ctr Invest Biomed Red Enfermedades Raras CIBERER, C Eduardo Primo Yufera 13, Valencia 46012, Spain
Univ Valencia, Dept Med, Avd Blasco Ibanez 15, Valencia, Spain
:
Ctr Invest Biomed Red Enfermedades Raras CIBERER, C Eduardo Primo Yufera 13, Valencia 46012, Spain
CIPF, Program Rare & Genet Dis, C Eduardo Primo Yufera 13, Valencia 46012, Spain
CIPF, IBV CSIC Associated Unit, C Eduardo Primo Yufera 13, Valencia 46012, Spain
Hosp St Joan de Deu, Dept Genet & Mol Med, P St Joan de Deu 2, Barcelona 08950, Spain
Hosp St Joan de Deu, Pediat Inst Rare Dis IPER, P St Joan de Deu 2, Barcelona 08950, Spain
:
Ctr Invest Biomed Red Enfermedades Raras CIBERER, C Eduardo Primo Yufera 13, Valencia 46012, Spain
CIPF, Program Rare & Genet Dis, C Eduardo Primo Yufera 13, Valencia 46012, Spain
CIPF, IBV CSIC Associated Unit, C Eduardo Primo Yufera 13, Valencia 46012, Spain
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