Mutations in theMORC2gene cause axonal Charcot–Marie–Tooth disease

Abstract

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.

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

“…11 They also report the MORC2 (p.R190W) mutation, which is the same as the p.R252W described in our largest family CMT105. No pyramidal signs were described in their families.…”

“…Annotations of the MORC2 mutations reported by Sevilla et al are based on the human MORC2 isoform 3, which encodes a shorter isoform of 970 amino acids (NM_014941.2). 11 …”

Characterising the phenotype and mode of inheritance of patients with inherited peripheral neuropathies carrying MME mutations

“…The multifocal pattern of myelinated fibres loss found in the nerve biopsy of patient F4/II:2 has been described in other CMT2 neuropathies like MORC2. 13 In general, we consider that MME -CMT is predominantly an axonal neuropathy although in some patients, especially in the median nerve, there are both axonal and demyelinating features probably reflecting the complex interaction between axons and Schwann cells not infrequently found in other genetic neuropathies. Neuropathies caused by mutations in MME have a clinical phenotype that can be easily confused with an acquired neuropathy, especially due to their age of onset and their relatively rapid progression, unlike classic CMT.…”

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

“…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.…”