Mutations in the MORC2 gene cause axonal Charcot-Marie-Tooth disease
Por:
Sevilla T, Lupo V, Martínez-Rubio D, Sancho P, Sivera R, Chumillas MJ, García-Romero M, Pascual-Pascual SI, Muelas N, Dopazo J, Vílchez JJ, Palau F and Espinós C
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:
Sevilla T:
1 Department of Neurology, Hospital Universitari i Politècnic La Fe, Avd. Fernando Abril Martorell no. 106, 46026 Valencia, Spain 2 Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), c/ Eduardo Primo Yúfera no. 13, 46012 Valencia, Spain 3 Department of Medicine, University of Valencia, Avd. Blasco Ibáñez no. 15, 46010 Valencia, Spain
Lupo V:
2 Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), c/ Eduardo Primo Yúfera no. 13, 46012 Valencia, Spain 4 Program in Rare and Genetic Diseases and IBV/CSIC Associated Unit, Centro de Investigación Príncipe Felipe (CIPF), c/ Eduardo Primo Yúfera no. 13, 46012 Valencia, Spain
Sivera R:
1 Department of Neurology, Hospital Universitari i Politècnic La Fe, Avd. Fernando Abril Martorell no. 106, 46026 Valencia, Spain
Chumillas MJ:
2 Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), c/ Eduardo Primo Yúfera no. 13, 46012 Valencia, Spain 5 Department of Clinical Neurophysiology, Hospital Universitari i Politècnic La Fe, Avd. Fernando Abril Martorell no. 106, 46026 Valencia, Spain
García-Romero M:
6 Department of Neuropaediatrics, Hospital Universitario La Paz, P° de la Castellana no. 261, 08046 Madrid, Spain
Pascual-Pascual SI:
6 Department of Neuropaediatrics, Hospital Universitario La Paz, P° de la Castellana no. 261, 08046 Madrid, Spain
Muelas N:
1 Department of Neurology, Hospital Universitari i Politècnic La Fe, Avd. Fernando Abril Martorell no. 106, 46026 Valencia, Spain 2 Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), c/ Eduardo Primo Yúfera no. 13, 46012 Valencia, Spain
Dopazo J:
2 Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), c/ Eduardo Primo Yúfera no. 13, 46012 Valencia, Spain 7 Program on Computational Genomics, Centro de Investigación Príncipe Felipe (CIPF), c/ Eduardo Primo Yúfera no. 13, 46012 Valencia, Spain
Vílchez JJ:
1 Department of Neurology, Hospital Universitari i Politècnic La Fe, Avd. Fernando Abril Martorell no. 106, 46026 Valencia, Spain 2 Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), c/ Eduardo Primo Yúfera no. 13, 46012 Valencia, Spain 3 Department of Medicine, University of Valencia, Avd. Blasco Ibáñez no. 15, 46010 Valencia, Spain
Palau F:
2 Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), c/ Eduardo Primo Yúfera no. 13, 46012 Valencia, Spain 4 Program in Rare and Genetic Diseases and IBV/CSIC Associated Unit, Centro de Investigación Príncipe Felipe (CIPF), c/ Eduardo Primo Yúfera no. 13, 46012 Valencia, Spain 8 Department of Genetic and Molecular Medicine, and Pediatric Institute for Rare Diseases (IPER), Hospital Sant Joan de Déu, P° Sant Joan de Déu no. 2, 08950 Barcelona, Spain
Espinós C:
2 Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), c/ Eduardo Primo Yúfera no. 13, 46012 Valencia, Spain 4 Program in Rare and Genetic Diseases and IBV/CSIC Associated Unit, Centro de Investigación Príncipe Felipe (CIPF), c/ Eduardo Primo Yúfera no. 13, 46012 Valencia, Spain
Green Submitted, Bronze
|