Mutation of a putative protein degradation gene LITAF/SIMPLE in Charcot-Marie-Tooth disease 1C.
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.
Street
V A
VA
V.M. Bloedel Hearing Research Center, Department of Otolaryngology-HNS, University of Washington, Seattle 98195, USA.
Bennett
C L
CL
Goldy
J D
JD
Shirk
A J
AJ
Kleopa
K A
KA
Tempel
B L
BL
Lipe
H P
HP
Scherer
S S
SS
Bird
T D
TD
Chance
P F
PF
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D015152:Blotting, Northern; D015153:Blotting, Western; D002607:Charcot-Marie-Tooth Disease / Q000235:genetics*; D002885:Chromosomes, Human, Pair 16 / Q000235:genetics; D003001:Cloning, Molecular; D004252:DNA Mutational Analysis; D005260:Female; D005786:Gene Expression Regulation; D005820:Genetic Testing; D006801:Humans; D008297:Male; D008565:Membrane Proteins; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D009416:Nerve Regeneration / Q000235:genetics; D009687:Nuclear Proteins; D009928:Organ Specificity; D010375:Pedigree; D011499:Protein Processing, Post-Translational; D017434:Protein Structure, Tertiary / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D012584:Sciatic Nerve / Q000254:growth & development / Q000378:metabolism / Q000473:pathology; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics*
C118738:LITAF protein, human; D008565:Membrane Proteins; D009687:Nuclear Proteins; D014157:Transcription Factors