Mouse models of Charcot-Marie-Tooth disease

Yosuke TanakaNobutaka Hirokawa*Dept of Cell Biology and

Anatomy, Graduate School

of Medicine, University of

Tokyo, Hongo, Tokyo

113-0033 Japan.

*e-mail: hirokawa@

m.u-tokyo.ac.jp

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0167-7799/02/$ – see front matter ©2002 Elsevier Science Ltd. All rights reserved. PII: S0168-9525(02)02839-1

IntroductionCharcot-Marie-Tooth disease (CMT) is the most common

of hereditary peripheral neuropathies with a prevalence

of 1:2500.The disease is inherited in an autosomal domi-

nant, recessive, or X-linked manner, and is included in a

disease category of hereditary motor-sensory neuropathy

(HMSN). Due to an impairment of peripheral neurons,

affected people progressively develop a weakness of pe-

ripheral muscles and become unable to walk. Muscular at-

rophy of distal muscles of the legs gives a characteristic

feature to the ankles called ‘inverted Champagne bottle

sign’. Weakness of peroneal muscle also makes the foot

arch higher, and induces a skeletal anomaly called ‘pes

cavus’ (or claw foot). Since its first description by three

great neurologists, Jean Martin Charcot (1825–1893),

Pierre Marie (1853–1940) and Howard Henry Tooth

(1926–1956), the primary causes of this disease have

been obscure; that is, until the past decade, when posi-

tional cloning of the responsible genes was achieved.

Orthopedic surgery has been almost the only effective

therapeutic approach for the symptoms of this disease.

The peripheral nervous system (PNS) mainly consists of

neurons and Schwann cells. A Schwann cell is a peripheral

form of glia, which produces a long protrusion called

myelin sheath that enrolls the neuronal axons. Schwann

cells also provide neurons with nutrition and neuro-

trophins, which are essential for neuronal survival and

function.Thus, neurons themselves, as well as the support-

ing Schwann cells, can be the primary site of peripheral

neuropathy.Although each of these could finally cause neu-

ronal degeneration and muscular atrophy, these different

pathologies can be distinguished by measuring the motor

nerve conduction velocity (MNCV), because a demyelina-

tion causes the loss of the electrical insulation provided by

the myelin sheath, impairing the saltatory conduction of

the axons. Using this criterion, CMT has been classified

into two major categories: patients with myelin impair-

ment (myelinopathy) have a low MNCV; whereas those

with neuronal impairment (axonopathy) maintain normal

MNCV. The former is mainly classified to CMT type I

(CMT1; HMSNI), and the latter is classified to CMT type II

(CMT2; HMSNII). Some other subtypes of CMT develop

hearing loss or vocal cord paralysis as well as characteristic

symptoms (see review by Benstead and Grant1).

Using linkage mapping for patient pedigrees, the re-

sponsible gene loci have been mapped on human chro-

mosomes, based on which, the subtypes of the disease

have been further classified. In the past five years, postge-

nomic approaches to the study of the human genome

have successfully determined the candidate genes for the

major subtypes, as summarized in Table 1. In this review,

we focus on the latest findings obtained from studies

using mouse models of CMT, including our recent discov-

ery of the gene responsible for CMT2A, and the involve-

ment of axonal transport in the pathogenesis of CMT2.

CMT1 mouse models with dysfunction ofSchwann cellsCMT1A models: PMP22 spontaneous mutantand transgenic linesCMT1A is one of the most extensively studied CMTs, with

the onset of the clinical symptoms occurring at approxi-

mately 12 years of age, and caused by overexpression or

Mouse models of Charcot-Marie-Tooth diseaseYosuke Tanaka and Nobutaka HirokawaA common peripheral neuropathy, Charcot-Marie-Tooth disease, progressively develops with distal muscle atrophy. Severalgenes expressed in Schwann cells and neurons have been identified to be responsible for this hereditary disease, and usedin generating transgenic and knockout mice. Such mice are good disease models for cell biological and therapeutic studies.

ALS: amyotrophic lateral sclerosisCH: congenital hypomyelination CMT: Charcot-Marie-Tooth diseaseCNS: central nervous systemDSS: Dejurine-Sottas syndromeGjb1: gap junction membrane channel protein beta 1HMSN: hereditary motor-sensory neuropathyKIFs: kinesin superfamily proteinsMNCV: motor nerve conduction velocityMPZ: myelin protein zeroPMP22: peripheral myelin protein 22PNPP: peripheral nerve pressure palsyPNS: peripheral nervous systemPRX: periaxinNFH: neurofilament, heavy polypeptideNFL: neurofilament, light polypeptideNFM: neurofilament, medium polypeptide

Abbreviations

In association with MKMD

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point mutation of a myelin integral membrane protein,

peripheral myelin protein 22 (PMP22).

CMT1A patients with duplication of genomic loci

encoding PMP22 develop peripheral neuropathy with a de-

creased MNCV2. Their peripheral nerves show a character-

istic onion-bulb appearance (Fig. 1), that is, rings of myelin

sheath around the neuronal axons, representing repeated

cycles of demyelination and remyelination. Homozygous

duplication and some point mutations of PMP22 also cause

a more severe form, Dejurine-Sottas syndrome (DSS or

HMSN III), which is defined by early onset, low MNCV and

severe disability. Conversely, those with a haploinsufficiency

of PMP22 develop a distinct entity of neuropathy, peripheral

nerve pressure palsy (PNPP)3, which develops after pro-

longed kneeling, and has a characteristic tomacula or a

sausage-like degeneration of peripheral myelin sheath.

PMP22 mouse models have been successfully gener-

ated using both forward and reverse genetic approaches

as described below.

Using classical forward genetics, Trembler (tre) and

Trembler-Jackson (tre-J) spontaneous mutant mice have

long been treated as a good peripheral neuropathy

model with abnormal gait. They were found to carry

mutations of G150D and L16P, respectively, in the

PMP22 protein4. Vallat et al.5 have analyzed the levels of

various myelin proteins in tre/+ mice, and found that

the PMP22 level is slightly lower than the normal level,

so that this point mutation would result in the gain-of-

function of PMP22. Using another forward genetics ap-

proach, Isaacs et al.6 performed a large-scale mouse ENU

mutagenesis screening, and found that two strains Tr-

m1H and Tr-m2H suffering from resting tremor carry

mutations in the PMP22 gene. Interestingly, the Tr-m1H

strain had a mutation of the same amino acid found in a

family with DSS (H12R).

Using reverse genetics, several lines of transgenic

mouse and rat models overexpressing PMP22 have been

established7–9, all of which develop an abnormal gait with

Table 1. Major genes responsible for CMT and related diseases

Gene symbol Chromosome OMIM Major mutations* Mouse models

PMP22 17p13-p12 601097 CMT1A Tr, TrJ, tg, tg (tTA)

PNPP KO

DSS ENU mutants

CMT and deafness

MPZ 1q22 159440 CMT1B KO, tg

DSS

CH

PRX 19q13.1-q13.2 605725 CMT4F KO

DSS

Gjb1; Cx32 Xq13.1 304040 CMTX KO

MTMR2 11q22 603557 CMT4B

NDRG1; Proxy1 8q24.3 605262 HMSNL

KIF1B 1p36.2 605995 CMT2A KO

NFL 8p21 162280 CMT2E KO, tg

GDAP1 8q13-q21.1 606598 CMT4A

Neuropathy with vocal cord paralysis

LMNA 1q21.2 150330 CMT2B1 KO

Emery-Dreifuss Muscular Dystrophy

Dilated Cardiomyopathy

Limb Girdle Muscular Dystrophy

*Major mutations were obtained from the OMIM database, available online at http://www.ncbi.nlm.gov/OMIM/searchomim.html. Abbreviations: CMT, Charcot-Marie-Tooth disease; PNPP, peripheral nerve pressurepalsy; DSS, Dejurine-Sottas syndrome; CH, congenital hypomyelination; HMSNL, hereditary motor and sensoryneuropathy, Lom-type; KO, knockout; tg, transgenic.

Figure 1. Onion-bulbappearance ofperipheral nerve inhypertrophicneuropathy

A cross section of peripheralnerve of a 10-year-old girlpresumably suffering fromCMT1A. Upon repeatedregeneration process of theaffected myelin sheath, three tofive layers of Schwann cellprocesses (asterisks) werefound to be circumferentiallyarranged around a small axon(Ax) with a myelin sheath (M).The processes are markedly flatand electron dense, and areseparated by connective tissue.Reproduced, with permission,from Schröder, J. M. (2001)Pathology of Peripheral Nerves,Springer-Verlag.



demyelinating progressive peripheral neuropathy, reveal-

ing the toxicity of excess PMP22 protein in Schwann

cells. The PMP22 knockout mouse shows irregular, volun-

tary stretching of the hindlimbs and trembling, which

may mimic PNPP.

Recently, Perea et al.10 generated transgenic mice that

conditionally overexpress the PMP22 protein using the

tet-off system. They generated two transgenic lines with:

(1) a Schwann-cell-specific expression of tTA, which is

composed of tetracycline repressor (TetR) and the VP16

activation domain; and (2) a PMP22 expression regulated

by the tetracycline operator (PhCMV*-1-PMP22); and

then crossed the two lines together. The resulting double

transgenic mice overexpress PMP22 under normal condi-

tions and develop neuropathy, but upon administration of

tetracycline-containing foods, the transgene can be

switched off. Using this system, they showed that inactiva-

tion of the transgene induces remyelination of peripheral

nerves of mice that had suffered from neuropathy.

Other models of myelin-based CMTsCMT1-related myelinopathic peripheral neuropathy is

also caused by mutations of several structural proteins in

Schwann cells (Fig. 2). Myelin protein zero (MPZ; P0),

periaxin (PRX) and gap junction membrane channel

protein beta 1 (Gjb1/connexin 32) are responsible for

CMT1B, CMT4F and CMTX, respectively, and mouse

models have been generated as reported in the following

text. MPZ is an immunoglobulin-related 28-kD integral

membrane glycoprotein of Schwann cells. It is a major

protein of the PNS, but is not expressed in the central ner-

vous system (CNS). K96E and D90E point mutations were

identified in pedigrees of autosomal dominant CMT1B

patients11, and the Mpz knockout mouse has served as a

model of CMT1B12 — both in homozygous and het-

erozygous states. Mpz(−/−) mice are deficient in normal

motor coordination and exhibit tremors and occasional

convulsions, and have severely impaired myelin formation

in peripheral nerve axons. In the case of Mpz(+/−) mice,

the myelin sheath seems normally formed initially but it

gradually thins after four weeks of age13.

PRX is a constituent of the dystroglycan-dystrophin-re-

lated protein-2 complex, which links the Schwann cell

cytoskeleton to the extracellular matrix14, and its muta-

tions cause a recessive demyelinating neuropathy, CMT4F.

Similar to the Mpz(+/−) mice, Prx(−/−) mice initially

myelinate normally but later develop a demyelinating peri-

pheral neuropathy15. Prx(−/−) mice show a pronounced

unsteadiness in the gait by six to nine months of age, los-

ing the body weight and suffering from neuropathic pain.

Gjb1 is a component of the gap junction, a major

intercellular channel for transmitting small molecules or

ions. In Schwann cells, Gjb1 is localized near the nodes of

Ranvier and in Schmitt-Lanterman incisures, which may

connect adjacent layers of the myelin sheath. Bergoffen et

al.16 described that a point mutation of Gjb1 is responsi-

ble for an X-linked dominant demyelinating neuropathy,

CMTX. A knockout mouse model for CMTX has been

established by Nelles et al.17. Gjb1(−/−) mice develop sig-

nificant reduction in body and brain weight, enhanced

intrinsic excitability of neurons, and demyelinating pe-

ripheral neuropathy after four to six months of age,

showing an onion-bulb appearance of the myelin sheath,

thinned myelin layers, and abnormally thick periaxonal

collars18. The sensory impairment is more moderate than

that in Mpz(+/−) mice18. Some other responsible genes

are myotubularin-related protein-2 (MTMR2) for CMT4B

or N-myc downstream-regulated gene 1 (NDRG1) for

HMSN-Lom (see Table 1), for which mouse models have

not yet been generated.

A transcription factor with three tandem zinc finger

motifs was found to be involved in CMT-like demyelinat-

ing peripheral neuropathy: mutations of early growth re-

sponse 2 (EGR2) have been detected in patients of CMT1,

DSS, and congenital hypomyelination (CH). Its mouse

homolog Krox20 was found to function in hindbrain

development, as seen through marked expression in

rhombomeres 3 and 5, and to also function in PNS

myelinogenesis. Krox20(−/−) mice show various pheno-

types in hindbrain segmentation, bone formation, growth

retardation, and neurology, with retarded performance

and tremors. The differentiation of peripheral Schwann

cells is affected and shows an amyelination19,20, as

expected from the localization of Krox20.

Finally, a xenograft experiment has been performed by

Sahenk and Chen21. They grafted CMTX patients’ sural

nerve segments into cut ends of the sciatic nerves of a nude



mouse. Since the nerve segments contained the nuclei of

Schwann cells, but not those of neurons, the regeneration

of murine sciatic nerve would mainly reflect on the activ-

ity of patients’ Schwann cells. As the nude mouse cannot

generate mature T lymphocytes due to a lack of the thy-

mus, it was able to serve as a recipient of the xenograft.

Results showed that the myelin sheath from axonopathic

CMT2 patients as well as from normal controls could suc-

cessfully induce the innervation of murine nerves, while

myelin sheath from myelinopathic CMTX patients could

not, suggesting that the myelin sheath from CMTX pa-

tients is indeed essential for developing neuropathy. This

could also be considered as an interesting experimental

model of demyelinating neuropathy.

CMT2 mouse models with dysfunction of neuronsA molecular motor for axonal transport —KIF1Bββ — is responsible for CMT2AIn contrast to the CMT1 diseases arising from Schwann

cell dysfunction, CMT2 occurs due to the dysfunction of

neurons themselves. The cytoskeleton is a filamentous

protein network that is essential for cellular morphogene-

sis and intracellular transport22.

Recently, two proteins associated with axonal cyto-

skeleton have been identified as being involved in the

pathogenesis of CMT2 (Fig. 3).

We have recently found that axonal transport is in-

volved in CMT2 pathogenesis through our research of

molecular motors. Neurons transport essential organelles

and protein complexes to their axons, using microtubule

motors that include approximately 50 kinds of kinesin

superfamily proteins (KIFs)23,24. A recently identified KIF

isoform, KIF1Bβ, is the motor for synaptic vesicle precur-

sors and responsible for CMT2A pathogenesis25. kif1B(−/−)

mice suffer from severe neuronal degeneration in the CNS,

which causes fatal newborn apnea. Of the two splicing

isoforms of the kif1B gene, only the KIF1Bβ isoform can

rescue neuronal death in primary culture.

kif1B(+/−) mice develop progressive muscle weakness

with a MNCV within the normal range, resembling the

symptoms of CMT2. Through a cell biological approach,

we found that KIF1Bβ binds to membrane organelles

containing synaptic vesicle proteins. We then compared

the level of synaptic vesicle proteins that are transported

to nerve endings by immunoblotting sciatic nerve lysate,

and found that the levels of both the cargo synaptic vesi-

cle proteins and the KIF1Bβ motor indeed decreases in

the peripheral axons of kif1B(+/−) mice. Since the human

KIF1B gene was mapped within the interval in which

CMT2A had been mapped, we collaborated with clinical

departments to analyze the genome of patient pedigrees,

and found a loss-of-function mutation of the motor

domain (Fig. 4). Since this dysfunctional motor did not

tightly bind to the track microtubules, loss-of-function as

opposed to a dominant negative mechanism explains the

development of CMT2A in this patient.

Accordingly, in CMT2A patients and kif1B(+/−) mice,

haploinsufficiency of the KIF1Bβ motor results in a defi-

ciency of the cargo proteins being transported by this

motor, including synaptic vesicle proteins in nerve axons

and endings, bringing about progressive dysfunction of

peripheral neurons.

Neurofilament L protein is involved in CMT2ERecently, point mutations of the neurofilament L (NFL)

protein have been found to be responsible for a domi-

nantly inherited CMT2E neuropathy26. Neurofilament

triplets (NFH, NFM, NFL) copolymerize to generate bun-

dles of intermediate filaments that are important compo-

nents of the neuronal cytoskeleton; thus, it is reasonable

to assume that mutations of NFL can cause a peripheral

neuropathy. Knockout mice for NFH and NFM have already

been established by several groups, although their pheno-

types are slightly different from each other, possibly

reflecting the difference in the gene targeting strategy

used (see review by Hirokawa and Takeda27). Moreover,

the mouse overexpressing the human NFH gene was es-

tablished by Julien and colleagues28 and has long been

treated as a classical mouse model for amyotrophic lateral

sclerosis (ALS), which causes neuronal swelling.

Julien and colleagues29 further established an NFL

knockout mouse but its phenotype was not so severe as

expected from human patients. When they axotomized

peripheral nerves, regeneration of myelinated axons was

Figure 2. Schematicrepresentation of across section of amyelinated axon

A process from a Schwann cellenrolls neuronal axons, formingthe myelin sheath. Mutations instructural proteins of the myelinsheath and a transcription factorEGR2 are responsible for themyelinopathic CMT1.

Figure 3. Axonalcytoskeleton isessential for CMT2pathogenesis

Two major components of theaxonal cytoskeleton, microtubule(MT) and neurofilament (NF) aresupporting unique protrudingmorphology of an axon. They arecrosslinked together like aladder with microtubule-associated proteins andsubunits of neurofilaments.Synaptic vesicle proteins aretransported via the MT trackswith a membrane organellecalled synaptic vesicleprecursor (SVP) by a molecularmotor KIF1Bβ. Mutations ofNFL and KIF1Bβ areresponsible for CMT2E andCMT2A, respectively. Adapted,with permission, from Wiley(Ref. 22).



found to be delayed. Thus, this simple knockout mouse

does not completely mimic the CMT patients’ pheno-

type. Future genetic and biochemical approaches, such

as introducing subtle mutations that have been charac-

terized from patients, would greatly facilitate the exami-

nation of how those mutations can alter the kinetics of

neurofilament assembly.

Future perspectivesHere, we have briefly reviewed the recent progress made

in positional cloning of candidate genes responsible for

CMT along with generation of their mouse models. Most

of the genes are found to encode structural and functional

proteins in Schwann cells and neurons. PMP22, MPZ,

GJB1 and PRX are the proteins localized in the myelin

sheath, and EGR2 may regulate the expression of essential

proteins in Schwann cells. KIF1Bβ and NFL are, respec-

tively, the microtubule motor and neuronal cytoskeletal

component that are highly expressed in neurons.

On the other hand, conventional criteria for the differ-

ential diagnosis between HMSN I, II, and others, are es-

sentially based on the symptoms of patients. For example,

DSS or HMSN III is an early onset and more severe form

of CMT. However, recent molecular approaches have iden-

tified that the same gene, for example, PMP22, with differ-

ent point mutations, is responsible for multiple diagnoses

of HMSN as summarized in Table 1. Moreover, the distinc-

tion between myelinopathy and axonopathy is sometimes

obscure, because some proteins are essential for both

neurons and Schwann cells30. Conversely, patients with

the same HMSN diagnosis could carry different mutations

in different genes. These multiple relationships between

differential diagnoses and candidate genes should be pre-

cisely redefined through accumulation of point mutation

data obtained by high-throughput SNP genotyping of

CMT patients.

Most of the current mouse models have been gener-

ated using transgenic techniques and homologous recom-

bination. Because, in many cases, the gene dosage affects

the severity of the disease, as in the case of PMP22, the

homologous recombination technique is more favorable

for a stable gene expression level, although this takes more

effort and time than simple transgenics. However, as in the

case of NFL, simple knockouts cannot always mimic the

disease phenotype because of the existence of a dominant

negative effect. Thus, generation of a series of knock-in

mice with a subtle mutation or SNP that has been charac-

terized from patient pedigrees will be the next step. For

introducing such subtle mutations, the cre-mutated-loxP

technology will enable us to easily introduce different

expression units into a specific site that is primarily

defined by a single homologous recombination31.

Two strains of different mouse models can be crossed

together. Suter and colleagues generated Mpz(+/−);

Gjb1(−/−) and Mpz(−/−);Gjb1(−/−) mice to demonstrate

that the demyelination process is accelerated in these dou-

ble knockout mice32. Although a single mutation would

be sufficient for the occurrence of human CMT, a double

mutation study in the mouse will still be fruitful to reveal

functional relationship between the two genes.

How will the mouse models be used in future studies?

They can be used for both basic and application studies.

For basic research, mutations could be a key to analyzing

the protein function. As was applied to the KIF1B study25,

biochemical and cell biological approaches will help in

determining how certain residues function, such as the

catalytic core, protein–protein interaction site or modifi-

cation site. Cell lines or primary cultured cells from the

mouse models will be a powerful tool for analyses that

will further clarify molecular machines that power the

functions of neurons and Schwann cells.

Regarding the clinical application of mouse models,

information on the mutated residues will be applied to

gene diagnosis and therapeutic trials. The study of a con-

Figure 4. Dysfunctional motor proteins with a CMT2A mutation

Immunofluorescence of Vero cells transfected with either wild-type or Q98L mutant KIF1Bβ constructs.Red and green signals indicate KIF1Bβ and tubulin, respectively. Healthy motors drive to and accumulateat the cell periphery where the microtubule tracks end, while the Q98L mutant motor remains at the cellcenter (arrows). Thus, the KIF1Bβ-Q98L mutant motor cannot transport synaptic vesicle precursors tothe axons. Bar: 15 µm. Reproduced, with permission, from Cell (Ref. 25).



ditional transgenic mouse for PMP22 suggests that some

forms of CMT1A can be reversed10, that is, silencing of

PMP22 overexpression can induce remyelination of pe-

ripheral nerves. This interesting finding should stimulate

the application of the tetracycline system on other types

of CMT mouse models, to test whether the pathological

defects are irreversible or not. These mice and their pri-

mary cultured cells will be useful for developing new

drugs for peripheral neuropathy. Antisense drugs will also

be potentially effective, but sufficient care should be taken

because an excessive reduction of the protein expression

level by antisense oligos could cause a PNPP neuropathy

as an adverse effect.

CMT has long been considered an incurable disease of

unknown cause. In this postgenomic era, great successes in

positional cloning studies have finally revealed the genes

responsible for this disease. The series of mouse models

generated to date are opening the door to its gene therapy,

as well as providing further knowledge concerning the

molecular and cell biological mechanism of how Schwann

cells and neurons work together to maintain the PNS.

AcknowledgementsWe thank Dr. Michael Schroeder (University Clinic

RWTH, Aachen, Germany) for permitting us to reproduce

an eletronmicrograph from his atlas.The study on CMT2A

was supported by a COE grant-in-aid from the Ministry

of Education, Culture, Sports, Science and Technology of

Japan to N.H.

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Mouse models of Charcot-Marie-Tooth disease