CMT4D disease is a severe autosomal recessive demyelinating neuropathy with 
extensive axonal loss leading to early disability, caused by mutations in the 
N-myc downstream regulated gene 1 (NDRG1). NDRG1 is expressed at particularly 
high levels in the Schwann cell (SC), but its physiological function(s) are 
unknown. To help with their understanding, we characterise the phenotype of a 
new mouse model, stretcher (str), with total Ndrg1 deficiency, in comparison 
with the hypomorphic Ndrg1 knock-out (KO) mouse. While both models display 
normal initial myelination and a transition to overt pathology between weeks 3 
and 5, the markedly more severe str phenotype suggests that even low Ndrg1 
expression results in significant phenotype rescue. Neither model replicates 
fully the features of CMT4D: although axon damage is present, regenerative 
capacity is unimpaired and the mice do not display the early severe axonal loss 
typical of the human disease. The widespread large fibre demyelination coincides 
precisely with the period of rapid growth of the animals and the dramatic 
(160-500-fold) increase in myelin volume and length in large fibres. This is 
followed by stabilisation after week 10, while small fibres remain unaffected. 
Gene expression profiling of str peripheral nerve reveals non-specific secondary 
changes at weeks 5 and 10 and preliminary data point to normal proteasomal 
function. Our findings do not support the proposed roles of NDRG1 in growth 
arrest, terminal differentiation, gene expression regulation and proteasomal 
degradation. Impaired SC trafficking failing to meet the considerable demands of 
nerve growth, emerges as the likely pathogenetic mechanism in NDRG1 deficiency.