Type 1 C Mutations Research News

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Abstract From Neurology 2003 Jan 14;60(1):22-6

Mutation of a putative protein degradation gene LITAF/SIMPLE in

Charcot-Marie-Tooth disease 1C.

Street VA, CL, Goldy JD, Shirk AJ, Kleopa KA, Tempel BL, Lipe

HP, Scherer SS, Bird TD, Chance PF.

V.M. Bloedel Hearing Research Center (Drs. Street and Tempel),

Department of Otolaryngology-HNS, University of Washington, Seattle.

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.