Mutations in the MORC2 gene cause axonal Charcot-Marie-Tooth disease.
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.
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.
Teresa
T
Sevilla
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 cespinos@cipf.es.
Vincenzo
V
Lupo
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.
Dolores
D
Martínez-Rubio
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.
Paula
P
Sancho
1 Department of Neurology, Hospital Universitari i Politècnic La Fe, Avd. Fernando Abril Martorell no. 106, 46026 Valencia, Spain.
Rafael
R
Sivera
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.
María J
MJ
Chumillas
6 Department of Neuropaediatrics, Hospital Universitario La Paz, P° de la Castellana no. 261, 08046 Madrid, Spain.
Mar
M
García-Romero
6 Department of Neuropaediatrics, Hospital Universitario La Paz, P° de la Castellana no. 261, 08046 Madrid, Spain.
Samuel I
SI
Pascual-Pascual
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.
Nuria
N
Muelas
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.
Joaquín
J
Dopazo
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.
Juan J
JJ
Vílchez
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.
Francesc
F
Palau
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 cespinos@cipf.es.
Carmen
C
Espinós
D000328:Adult; D000368:Aged; D000818:Animals; D001369:Axons / Q000473:pathology*; D002607:Charcot-Marie-Tooth Disease / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D005260:Female; D015870:Gene Expression / Q000235:genetics; D006801:Humans; D007223:Infant; D008297:Male; D051379:Mice; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D012584:Sciatic Nerve / Q000378:metabolism; D013497:Sural Nerve / Q000648:ultrastructure; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics*; D055815:Young Adult
C549896:MORC2 protein, human; D014157:Transcription Factors
Charcot-Marie-Tooth disease; MORC2 gene; Schwann cell; axonal degeneration; whole-exome sequencing