BACKGROUND: Charcot-Marie-Tooth (CMT) neuropathy is a heterogeneous group of 
inherited disorders of the peripheral nervous system. The authors recently 
mapped an autosomal dominant demyelinating form of CMT type 1 (CMT1C) to 
chromosome 16p13.1-p12.3.
OBJECTIVE: To find the gene mutations underlying CMT1C.
METHODS: The authors used a combination of standard positional cloning and 
candidate gene approaches to identify the causal gene for CMT1C. Western blot 
analysis was used to determine relative protein levels in patient and control 
lymphocyte extracts. Northern blotting was used to characterize gene expression 
in 1) multiple tissues; 2) developing sciatic nerve; and 3) nerve-crush and 
nerve-transection experiments.
RESULTS: The authors identified missense mutations (G112S, T115N, W116G) in the 
LITAFgene (lipopolysaccharide-induced tumor necrosis factor-alpha factor) in 
three CMT1C pedigrees. LITAF, which is also referred to as SIMPLE, is a widely 
expressed gene encoding a 161-amino acid protein that may play a role in protein 
degradation pathways. The mutations associated with CMT1C were found to cluster, 
defining a domain of the LITAF protein having a critical role in peripheral 
nerve function. Western blot analysis suggested that the T115N and W116G 
mutations do not alter the level of LITAF protein in peripheral blood 
lymphocytes. The LITAF transcript is expressed in sciatic nerve, but its level 
of expression is not altered during development or in response to nerve injury. 
This finding is in stark contrast to that seen for other known genes that cause 
CMT1.
CONCLUSIONS: Mutations in LITAF may account for a significant proportion of CMT1 
patients with previously unknown molecular diagnosis and may define a new 
mechanism of peripheral nerve perturbation leading to demyelinating neuropathy.