Mutations in Trk-fused gene (TFG) have been implicated in both diseases, but the pathomechanisms by which these alterations cause neuropathy remain unclear.
Collectively, these data indicate that alterations at the premyelinating stage, linked to altered targeting of P0, may be responsible for CH, and that different types of gain of abnormal function produce the diverse neuropathy phenotypes associated with MPZ, supporting future allele-specific therapeutic silencing strategies.
Here we show that genetic overexpression of Nrg1TIII ameliorates neurophysiological and morphological parameters in a mouse model of demyelinating CMT1B, without exacerbating the toxic gain-of-function that underlies the neuropathy.
Moreover, we provide strong evidence that the Schwann cell-specific ablation of the ERAD factor Derlin-2 in S63del nerves exacerbates both the myelin defects and the UPR in vivo, unveiling a protective role for ERAD in CMT1Bneuropathy.
Charcot-Marie-Tooth disease, type 1B (CMT1B, OMIM 118200) is an autosomal dominant neuropathy caused by mutations in myelin protein zero (MPZ, OMIM 159440), a structural protein of peripheral myelin.
Our observation suggests that MPZ-related neuropathy should be considered in the diagnostic work up of patients with painful axonal neuropathy even presenting with rapid progression and at a very late age of onset.
Myelin protein zero is a key structural component of compact myelin, and over 100 mutations in this protein have been reported, which can give rise to neuropathies with either axonal, demyelinating, or intermediate features encompassing a wide range of severity.
R98C mice, an authentic model of early onset Charcot-Marie-Tooth disease type 1B, develop neuropathy in part because the misfolded mutant myelin protein zero is retained in the endoplasmic reticulum where it activates the unfolded protein response.
Elegant studies with Ser63del mice suggest that Ser63delMPZ is retained in the ER where it activates the unfolded protein response (UPR) that contributes to the neuropathy.
This case illustrates the clinical heterogeneity that exists in neuropathies associated with MPZ mutations and highlights that in patients with mild hypotonia in the first months that develop a very severe demyelinating neuropathy, the MPZ gene must be taken into account.
We report a patient with Charcot-Marie-Tooth disease (CMT) due to the p.Ile112Thr mutation in myelin protein zero (MPZ) who presented with a patchy neuropathy with conduction block and tonic pupils.
The Pro132Leu mutation segregates with a severe early-onset dysmyelinating-hypomyelinating neuropathy, whereas the Ile135Thr substitution is associated with the classical phenotype of CMT1.
We report two new MPZ mutations causing congenital hypomyelinating neuropathies; c.368_382delGCACGTTCACTTGTG (in-frame deletion of five amino acids) and c.392A>G, Asn131Ser.
We recommend testing for MPZ mutations in patients with a late-onset neuropathy, as late-onset inherited neuropathies might be more frequent than previously thought.
Charcot-Marie-Tooth disease (CMT) is a group of clinically and genetically heterogeneous neuropathies classically divided into demyelinating (CMT1) and axonal forms (CMT2).
Hereditary motor and sensory neuropathy (HMSN), also known as Charcot-Marie-Tooth disease (CMT) is a group of clinically and genetically heterogeneous neuropathies classically divided into demyelinating (CMT1) and axonal forms (CMT2).
Based on the age of onset, clinical and pathological features, most MPZ mutations are separable into two groups: one causing a severe, early-onset, demyelinating neuropathy and a second, causing a late-onset neuropathy with prominent axonal loss.
The results support the hypothesis that severe, early-onset neuropathy may be related to either an alteration of a conserved amino acid or a disruption of the tertiary structure of myelin protein zero.
Most mutations in the myelin protein zero gene (MPZ) typically cause a severe demyelinating/dysmyelinating neuropathy that begins in infancy or an adult-onset axonal neuropathy.
Intronic mutations cause CMT1B by disrupting splicing and certain MPZ mutations may cause neuropathy by interacting with the wild type MPZ in the extracellular space of compact myelin.