Trends in Genetics
ReviewMouse models of Charcot-Marie-Tooth disease
Introduction
Charcot-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 dominant, 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 peripheral muscles and become unable to walk. Muscular atrophy 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 positional 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 neurotrophins, which are essential for neuronal survival and function. Thus, neurons themselves, as well as the supporting Schwann cells, can be the primary site of peripheral neuropathy. Although each of these could finally cause neuronal degeneration and muscular atrophy, these different pathologies can be distinguished by measuring the motor nerve conduction velocity (MNCV), because a demyelination 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 impairment (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 responsible gene loci have been mapped on human chromosomes, based on which, the subtypes of the disease have been further classified. In the past five years, postgenomic 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 discovery of the gene responsible for CMT2A, and the involvement of axonal transport in the pathogenesis of CMT2.
Abbreviations
Section snippets
CMT1A models: PMP22 spontaneous mutant and transgenic lines
CMT1A is one of the most extensively studied CMTs, with the onset of the clinical symptoms occurring at approximately 12 years of age, and caused by overexpression or 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 decreased MNCV2. Their peripheral nerves show a characteristic onion-bulb appearance (Fig. 1), that is, rings of myelin sheath around the
A molecular motor for axonal transport — KIF1Bβ — is responsible for CMT2A
In 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 morphogenesis and intracellular transport22.
Recently, two proteins associated with axonal cytoskeleton have been identified as being involved in the pathogenesis of CMT2 (Fig. 3).
We have recently found that axonal transport is involved in CMT2 pathogenesis through our research of
Future perspectives
Here, 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, respectively, the microtubule motor and neuronal cytoskeletal
Acknowledgements
We 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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