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ILAR Journal V36(3/4) 1994 [FORMERLY ILAR NEWS]
Advances in Gene Therapy
Benjamin B. Roa and James R. Lupski
| Benjamin B. Roa, Ph.D., is a postdoctoral fellow in the Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas. James R. Lupski. M.D., Ph.D. is Associate Professor in the Depart-ment of Molecular and Human Genetics, Human Genome Center and De-partment of Pediatrics, Baylor College of Medicine, Houston. Texas. |
INTRODUCTION
Charcot-Marie-Tooth disease (CMT) is an inherited disorder of the peripheral nerves, which involves slowly progressive weakness and atrophy of the distal muscles (Charcot and Marie, 1886; Tooth, 1886). CMT is a type of hereditary motor and sensory neuropathy that exhibits both clinical and genetic heterogeneity (Dyck et al., 1993; Lupski et al., 1991a). Clinical features include initial weakness of the intrinsic foot and distal leg muscles, which lead to foot deformities and gait abnormalities. Later in the course of the disease, variable progressive weakness of the hands may occur (Dyck et al., 1993; Lupski et al., 1991a). CMT constitutes the most common inherited peripheral neuropathy with an estimated population frequency of 1:2500 (Skre, 1974). Studies on the molecular genetics of CMT have provided a wealth of information in recent years, which was facilitated by parallel developments in mouse models of the disease. This brief review will summarize the current findings, paying particular attention to CMT type lA, which is the major form of the disease. The molecular findings on CMT1A have revealed a novel mutational mechanism for an autosomal dominant human disorder. Furthermore, the gene responsible for CMT1A has been shown to be involved in two related peripheral neuropathies as well. The collective findings have furthered our understanding of the molecular bases of primary inherited peripheral neuropathies and have provided useful insights on the prospective development of strategies for gene therapy of CMT and related disorders.
GENETIC HETEROGENEITY OF CHARCOT-MARIE-TOOTH DISEASE
Two forms of CMT can be differentiated by electrophysiology. CMT type 1 (CMT1), or hereditary motor and sensory neuropathy type I (HMSNI) (Dyck et al., 1993), exhibits symmetrically reduced motor nerve conduction velocity (NCV) due to a defect in myelin of the peripheral nervous system (PNS) myelin'(Lupski and Garcia, 1992; Lupski et al., 1991a; Kaku et al., 1993a). Peripheral nerve biopsies in CMT1 patients show decreased myelination and hypertrophic changes with onion bulb formation, which consist of concentric membranes derived from Schwann cells surrounding myelinated and demyelinated internodes (Dyck et al., 1993; Lupski and Garcia, 1992; Lupski et al., 1991a). In contrast to demyelinating CMT1, the axonal form of the disease CMT2 (also known as HMSNII) exhibits normal or only mildly reduced motor NCV (Dyck et al., 1993; Lupski et al., 1991a). CMT represents a genetically heterogeneous collection of peripheral nerve disorders (McKusick, 1992), for which the genes responsible for subtypes CMT1A, CMT1B, and CMTX have been identified. The autosomal dominant CMT1A gene on chromosome 17pl 1.2-p12 was identified as PMP22, which encodes a peripheral nerve myelin protein of 22 kDa Mr (Matsunami et al., 1992; Patel et al., 1992; Roa et al., 1993a; Timmerman et al., 1992; Valentijn et al., 1992a, b). The CMT1B gene on lq21.2-q23 was identified to be MPZ encoding myelin protein zero (P0), which is reportedly the most abundant myelin protein in the peripheral nervous system that functions as a homophilic adhesion molecule in PNS myelin compaction (Hayasaka et al., 1993a, b ,c, d; Himoro et al., 1993; Kulkens et al., 1993). The locus for the X-linked form of CMT (CMTX) was identified as the Cx32 or GJB1 gene encoding the connexin-32 trans-membrane protein involved in the formation of gap junctions (Bergoften et al., 1993). CMT1A comprises the majority of cases ofCMT (Lupski et al., 1993a), and is particularly interesting as a novel paradigm for genetic disease (Patel and Lupski, 1994).
GENE DOSAGE AS A NOVEL MECHANISM FOR CMTIA
The disease phenotype of CMT1A is most commonly associated with a 1.5-Mb DNA duplication on chromosome 17pll.2-p12 (Lupski et al., 1991b; Pentao et al., 1992; Raeymaekers et al., 1991; Wise et al., 1993). Electrophysiological studies in CMT1A families showed a clear bimodal distribution between symmetrically decreased motor nerve conduction velocities in CMT1A duplication patients (<42 m/sec), and normal NCV in unaffected family members without the duplication (Kaku et al., 1993b). This cytogenetically undetectable DNA duplication was originally identified by molecular methods in U.S. and Northern European CMT1A failies (Lupski et al., 1991b; Raeymaekers et al., 1991). Subsequent studies confirmed the presence of the CMT1A duplication in patients of different ethnic backgrounds (Roa et al., 1993b). Furthermore, the CMT1A duplication was detected in 70-85% of unrelated CMT1 patients (Ionasescu et al., 1993a; Wise et al., 1993; Christine Van Broeckhoven, University of Antwerp, Belgium, European Neuromuscular disorders CMT Consortium Group, written communication, September 13, 1993). Moledular identification of the CMT1A duplication on 17;11.2-p12 thus constitutes a very useful diagnostic tool (Lupski et al., 1993).
The CMT1A duplication was frequently observed as a new mutation in CMT1 cases with no family history (Hoogendijk et al., 1992). The vast majority of CMT1A patients demonstrate a 500-kb SacII duplication junction fragment by pulsed-field gel electrophoresis, which indicates a uniform size of the CMT1A duplication (Lupski et al., 1991b, 1993b; Raeymaekers et al., 1991, 1992; Wise et al., 1993). These findings suggest that an intrinsic property of the genome at 17;11.2-p12 predisposes the region to DNA rearrangement. Physical mapping studies determined that the 3.0-Mb CMT1A duplication is a tandem duplication of a 1.5-Mb monomer unit on 17p11.2-p12 that is flanked by CMT1A-REP repeat sequences of approximately 30 kb (Chance et al., 1994; Pentao et al., 1992).
The reciprocal 1.5-Mb DNA deletion on 17p11.2-p12 is associated with hereditary neuropathy with liability to pressure palsies (HNPP), a clinically distinct demyelinating neuropathy that exhibits autosomal dominant inheritance (Chance et al., 1993). The boundaries for the CMT1A duplication and the HNPP deletion appear to lie at CMT1A-REP (Chance et al., 1994; Pentao et al., 1992). Moreover, southern analysis to detect dosage differences of CMT1A-REP restriction fragments has been useful in screening for the CMT1A duplication and the HNPP deletion. The CMT1A-REP repeats which are present in two copies on the normal chromosome, were shown to be present in three copies on the CMT1A duplication chromosome, and in only one copy on the HNPP deletion chromosome (Chance et al., 1994; Pentao et al., 1992).
The flanking CMT1A-REP repeated sequences apparently mediate reciprocal recombination events, whereby unequal crossing over at misaligned CMT1A-REPs on non-sister chromatids generates the CMT1A duplication or the HNPP deletion (Chance et al., 1994; Lupski et al., 1993a; Pentao et al., 1992). CMT1A can be described as a "genomic disease" in which local DNA structures predispose a specific genomic region to DNA rearrangements associated with disease. Furthermore, de novo CMT1A duplication events were observed to be of paternal origin, having arisen through unequal crossing over during spermatogenesis (Palau et al., 1993). In a similar manner, hemophilia A involves a discrete DNA arrangement wherein repeated sequences on Xq28 mediate an intrachromosomal inversion that disrupts the factor VIII gene (Lakich et al., 1993). This inversion rearrangement is also seen to arise almost exclusively in the male germline (Rossiter et al., 1994).
Several models have been proposed by which DNA duplication can lead to the CMT1A disease phenotype (Lupski et al., 1991b). However, the collective evidence is strongly in favor of the gene dosage mechanism wherein increased expression of a duplicated gene causes CMT1A (Lupski et al., 1992; Roa et al., 1993b). A rare homozygous CMT1A duplication patient was found to exhibit a more severe clinical phenotype compared to heterozygous CMT1A family members (Lupski et al., 1991b). In addition, four rare patients with different cytogenetically visible 17p duplications had symmetrically decreased nerve conduction velocities characteristic of CMT1A. This finding effectively rules out disruption of a critical gene at the CMT1A duplication boundary or secondary position effects as disease mechanisms. Instead, the data support increased dosage of a duplicated gene as the mechanism for disease (Chance et al., 1992; Lupski et al., 1992; Roa et al., 1993b; Upadhyaya et al., 1993). The PMP22 gene encoding a peripheral nerve myelin protein was mapped within the 1.5-Mb region that is duplicated in CMT1A, and was proposed to be the dosage-sensitive candidate gene (Matsunami et al., 1992; Patel et al., 1992; Timmerman et al., 1992; Valentijn et al., 1992b). In support of this hypothesis, three rare CMT1A patients with smaller 17p duplications were found to be duplicated for the PMP22 gene (Ionasescu et al., 1993b; Palau et al., 1993; [Valentijn et al., 1993). Moreover, slightly elevated levels of PMP22 mRNA expression relative to other myelin genes were observed in peripheral nerve biopsies from CMT1A duplication patients (Yoshikawa et al., 1994).
THE PMP22 GENE IN CMTIA AND RELATED PERIPHERAL NEUROPATHIES
The gene that is now referred to as PMP22 was originally isolated as the gas3 gene, which is preferentially expressed upon cell growth arrest in NIH3T3 mouse fibroblasts (Schneider et al., 1988). This gene encodes an integral membrane protein whose apparent molecular weight is increased to approximately 22 kDa by glycosylation (Manfioletti et al., 1990). The homologous rat cDNA clones designated as CD25 (Spreyer et al., 1991) and SR 13 (De Leon et al., 1991; Welcher et al., 1991) were isolated by subtractive hybridizations of rat sciatic nerve cDNA libraries, as genes that are downregulated following nerve injury. The mRNA developmental expression profile was shown to coincide with known myelin genes (De Leon et al., 1991), and the cDNA clones designated as SR13/CD25/gas3 were found to be homologous to the bovine myelin protein PASII (Kitamura et al., 1976). The term PMP22 was adopted for this gene which encodes a peripheral nervous system myelin protein of 22-kDa Mr that localizes to the compact portions of PNS myelin (De Leon et al., 1991). Furthermore, the PMP22 gene reisolated in the mouse was found to be identical to gas3(Suter et al., 1992a) after resolution of a frameshift error that appeared in the original gas3 sequence (Manfioletti et al., 1990).
Mutations in PMP22 were identified in the Trembler (Suter et al., 1992a) and the TremblerJ(TrJ) (Suter et al., 1992b) mouse mutants, which were considered to be animal models for human demyelinating peripheral neuropathies. The autosomal dominant Trembler (Tr) mouse mutation causes spastic paralysis of the legs and convulsions that occur upon stimulation (Falconer, 1951). Electrophysiological studies showed greatly reduced motor NCVs, and histological studies revealed decreased myelination with onion bulb formations (Low, 1977; Low and McLeod, 1975). The underlying defect resides in the Schwann cells, which generate abnormal peripheral nerve myelin and show persistent cell proliferation in adult Trembler mice (Aguayo et al., 1977; Perkins et al., 1981). The Tr mutation was mapped to mouse chromosome 11 in a syntenic region with human chromosome 17p, where CMT1A maps (Buchberg et al., 1989, 1991; Davisson and Roderick, 1978). Similarly, the (TrJ) mouse mutation mapped to mouse chromosome 1 I, showed semi-dominant expression, and elicited a hypomyelinating phenotype in the peripheral nerves, indicating that Tr and TrJ are allelic mutations (Henry et al., 1983). This was confirmed by the identification of allelic PMP22 point mutations in Trembler (Glyl50Asp) (Suter et al., 1992a), and TremblerJ (Leul6Pro) mice (Suter et al., 1992b), as listed in Table 1.
These developments facilitated the identification of human PMP22 as the CMT1A gene through a "positional candidate'' approach. The human PMP22 gene was mapped within the 1.5-Mb region on 17pl 1.2-p12 that is duplicated in CMT1A (Matsunami et al., 1992; Patel et al., 1992; Timmerman et al., 1992; Valentijn et al., 1992b). The cDNA clone for the human PMP22 was sequenced, which revealed a coding region for a 160 amino acid protein (Figure 1). Moreover, PMP22 mRNA was shown to be expressed at high levels specifically in peripheral nerve (Patel et al., 1992). The PMP22 gene is known to be highly expressed in differentiated Schwann cells, butis dramatically downregulated upon nerve injury resulting in loss of axon-Schwann cell contact (Spreyer et al., 1991; Welcher et al., 1991). Mutations in PMP22 were identified in CMT1 patients who did not carry the CMT1A duplication. A CMT1A family was identified with a PMP22 point mutation identical to that of TremblerJ mouse (Valentijn et al., 1992a). A de novo PMP22 point mutation was independently identified which leads to a serine-to-cysteine (Ser79Cys) substitution in PMP22 (Roa et al., 1993a). These autosomal dominant mutations cause non-conservative substitutions in well-conserved putative trans-membrane domains, which could lead to increased or altered PMP22 function (Roa et al., 1993a). The disease phenotype of CMT1A can therefore arise from alternative mutational mechanisms: DNA duplication of the region including PMP22, or point mutation of the PMP22 gene.
In addition to autosomal dominant mutations, an apparent recessive allele of PMP22 was associated with the CMTIA disease phenotype. A CMT1A patient in an unusual family was identified to be a compound heterozygote carrying a PMP22 point mutation on one chromosome, together with deletion of PMP22 and the surrounding 1.5-Mb region (the HNPP deletion) on the other chromosome (Roa et al., 1993c). The segregation pattern in this family suggested that the apparent recessive phenotype of this PMP22 mutation (Thr118Met) was "unmasked" by the deletion in the compound heterozygote (Roa et al., 1993c).
Mutations.in PMP22 are also associated with Dejerine-Sottas syndrome (DSS), which is a severe demyelinating neuropathy whose clinical, electrophysiological, and histological findings overlap with CMT1; however, the symptoms in DSS are more severe and of earlier onset than in CMT1 (Dejerine and Sottas, 1893; Dyck et al., 1993). A de novo mutation in PMP22 (Met69Lys), and a separate mutation (Ser72Leu) were identified in two unrelated DSS patients (Table 1) (Roa et al., 1993d). Alternatively, Dejerine-Sottas syndrome has also been associated with de novo point mutations in the MPZ myelin protein zero gene, which is the same gene responsible for CMT type lB (Hayasaka et al., 1993e). Although most DSS pedigrees appear to be consistent with autosomal recessive transmission, the heterozygous PMP22 and MPZ mutations suggest the action of autosomal dominant alleles (Roa et al., 1993d; Hayasaka et al., 1993e). These findings indicate that CMT1 and Dejerine-Sottas syndrome constitute a spectrum of related clinical phenotypes that can arise from allelic missense mutations in the PMP22 and the MPZ myelin genes (Roa et al., 1993d; Hayasaka et al., 1993e).
The PMP22 gene is also associated with hereditary neuropathy with liability to pressure palsies (HNPP) (Nicholson et al., 1994). This autosomal dominant demyelinating neuropathy is clinically characterized by episodes of prolonged numbness, muscular weakness, and atrophy following relatively minor compression or trauma to the peripheral nerves (Windebank, 1993). Mild reductions in NCV with evidence of conduction blocks may be observed by electrophysiology (Dyck et al., 1981). Histological findings include segmental demyelination of the peripheral nerves with characteristic tomacula or sausage-like focal thickenings of the myelin sheath (Windebank, 1993). The uncompacted myelin lamellae suggested that a defect in Schwann cell-axon interaction leads to the clinical findings in HNPP (Yoshikawa and Dyck, 1991). The majority of HNPP cases were found to be associated with a 1.5-Mb DNA deletion at 17p 11.2p 12 which includes the PMP22 gene (Chance et al., 1993; Roa et al., 1993c; Lorenzetti et al., 1995). The identification of a PMP22 frameshift mutation in a non-deletion HNPP patient (Table 1) demonstrated the direct involvement of the PMP22 gene (Nicholson et al., 1994).
The molecular findings strongly indicate that PMP22 is the principal dosage-sensitive gene within the 1.5-Mb CMTIA/HNPP region. Underexpression of the PMP22 gene, either through gene deletion (1/2 gene dosage) or nonsense mutations, results in the HNPP phenotype (Chance et al., 1993; Nicholson et al., 1994). On the other hand, a 1.5-fold increased dosage of the region containing the PMP22 gene is most commonly associated with CMT1A (Wise et al., 1993; Ionasescu et al., 1993a, b; Palau et al., 1993; Christine Van Broeckhoven, University of Antwerp. Belgium, European Neuromuscular Disorders CMT Consortium Group, written communication, September 13, 1993). Apart from gene duplication, mutations in PMP22 leading to single ammo acid substitutions elicit the related phenotypes of CMT1A and DSS (Valentijn et al., 1992a; Roa et al., 1993a, c, d). To reconcile these alternative mechanisms, we had proposed that nonconservative amino acid substitutions could alter the native PMP22 structure and function so as to disrupt the critical stoichiometry of PMP22 on the peripheral nerve membrane (Roa et al., 1993a, b). One possibility is that PMP22 point mutations lead to increased protein function that mimics the effect of increased gene dosage. Another possibility is that these mutations act as dominant negative alleles that interfere with PMP22 interactions in a multimeric complex. Although alterations in the PMP22 myelin gene clearly result in disease phenotypes, its exact biological function needs to be determined in order to understand how increased PMP22 dosage or gene mutation lead to demyelinating peripheral neuropathies.
THE PLP GENE AND NEUROPATHIES OF THE CENTRAL NERVOUS SYSTEM
The proteolipid protein (PLP) or lipophilin is a 30 kDa protein of central nervous system myelin (Lemke, 1988). Structural similarities between the PLP and PMP22 myelin proteins have been pointed out, although these proteins do not exhibit amino acid sequence homology (Suter et al., 1993). Figure 1 shows the proposed structural model for PMP22 (Suter et al., 1992b), and the controversial four-helix model for PLP (Popot et al., 1991). Figure 1 also shows the isoform DM20 (lacking 35 amino acids, MW of 26 kDa) that is generated by alternative splicing of the PLP gene (Nave et al., 1987a). Approximately half the protein in CNS myelin is comprised of PLP. This myelin protein is extremely well conserved, with 100% identity between the human and rodent PLP homologues (Lemke, 1988).
Structural mutations in the PLP gene, as well as gene dosage alterations, are associated with myelin disorders affecting the central nervous system (Table 1). The most commonly associated human disorder is X-linked Pelizaeus-Merzbacher disease (PMD) (McKusick, 1992), which was also referred to as the chronic infantile type of diffuse cerebral sclerosis. Symptoms of this slowly progressive CNS dysmyelinating disease include nystagmus, jerking and rolling head movements or tremors, ataxia, spasticity, optic atrophy, and premature death (McKusick, 1992). PMD is associated with point mutations in PLP leading to single amino acid substitutions (Table 1) that are situated largely within putative transmembrane domains (Gencic et al., 1989; Trofatter et al., 1989; Hudson et al., 1989; Bridge et al., 1991; Pham-Dinh et al., 1991; Pratt et al., 1991; Strautnieks et al., 1992; Doll et al., 1992; Pratt et al., 1993; Iwaki et al., 1993). A PLP frameshift mutation was also identified in a family with PMD (Pham-Dinh et al., 1993). In addition, PMD is also associated with increased or decreased dosage of the PLP gene. Deletion of PLP was demonstrated in affected males of one PMD family (Raskind et al., 1991), and DNA duplication leading to increased PLP gene dosage was identified in families with PMD (Cremers et al., 1987, 1988; Ellis and Malcolm, 1994). Therefore, the PLP and PMP22 genes share striking similarities in the structure of their respective myelin proteins, and in their sensitivity to amino acid substitutions or to gene dosage alterations that can lead to myelin-deficient neurological phenotypes.
The increased PLP gene dosage mechanism for Pelizaeus-Merzbacher disease was verified experimentally in transgenic mice that expressed extra copies of the normal PLP gene. The PLP overexpressing mice exhibited severe hypomyelination, seizures, and premature death, which are representative of the human PMD phenotype (Readhead et al., 1994; Kagawa et al., 1994). Studies in animal models, particularly in the mouse, contributed immensely to our understanding of PLP and PMP22. The biology of myelin proteolipid protein has been comprehensively reviewed elsewhere (Lemke, 1993; Nave et al., 1994). Mutations in PLP identified in a number of animal models are listed in Table 1. The jimpy mouse mutation is a single base change at the intron 4 splice acceptor of PLP, which leads to aberrant splicing and an unstable protein (Nave et al., 1987b; udson et al., 1987). The jimpy phenotype includes tremors and seizures, severe deficiency in CNS myelin, and premature death at about 30 days. Oligodendrocytes that produce CNS myelin develop abnormally and proliferate at a high rate, with the majority undergoing early cell death (Skoff, 1982; Knapp et al., 1986; ]Macklin et al., 1987). In contrast to the splicing mutation in the jimpy (jp) mouse, point mutations leading to single amino acid substitutions were identified in the jp myelin synthesis deficient (jpmsd) mouse (Gencic and Hudson, 1990), the rumpshaker mouse (rsh) (Schneider et al., 1992), the myelin-deficient rat (md) (Boison and Stoffel, 1990), and the shaking pup dog (Nadon et al., 1990) (Table 1). These mutant phenotypes are largely similar to the jimpy mouse, with the notable exception of the long-lived, myelin-deficient rumpshaker mouse (rsh) whose oligodendrocytes escape early cell death and appear to be morphologically normal (Schneider et al., 1992; Fanarraga et al., 1992).
The PLP gene was recently associated with X-linked uncomplicated spastic paraplegia (SPG2) (McKusick, 1992) whose clinical phenotype includes nystagmus, optic atrophy, mental retardation, and mild ataxia (McKusick, 1992). A PLP point mutation leading to the His139Tyr substitution was identified in an SPG2 family (Saugier-Veber et al., 1994), and a second SPG2 mutation (Ile186Thr) was found to be identical to the rsh mouse mutation (Table 1) (Kobayashi et al., 1994). Pelizaeus-Merzbacher disease and X-linked spastic paraplegia thus appear to be allelic disorders at the PLP locus (Saugier-Veber et al., 1994), in a similar manner that Charcot-Marie-Tooth disease type lA, Dejerine-Sottas syndrome, and HNPP are allelic at the PMP22 locus (Roa et al., 1993d).
IMPLICATIONS FOR PROSPECTIVE GENE THERAPY INVOLVING PMP22
While gene therapy is proving to be a viable option for a number of genetic diseases, the development of gene therapeutic strategies for Charcot-Marie-Tooth disease type lA and related PMP22 neuropathies face two formidable challenges: (1) the apparent dosage sensitivity of the PMP22 gene, and (2) the currently unknown function of PMP22 in peripheral nerve myelination. Since the majority of CMT1A cases are associated with DNA duplication (Wise et al., 1993; Ionasescu et al., 1993a), and specific increases in PMP22 gene expression were observed in CMT1A nerve biopsies ([Yoshikawa et al., 1994), a reasonable strategy could target downregulation of PMP22 gene expression through antisense constructs. A promising antisense strategy makes use of peptide nucleic acids (PNA) wherein nucleic acids incorporated into a polyamide backbone bind to complementary RNA in a 1:1 complex (Brown et al., 1994). However, a tight threshold effect appears to be involved, since PMP22 gene deletion or nonsense mutation (presumably resulting in a 50% reduction of gene expression) leads to the distinct disease phenotype of HNPP (Nicholson et al., 1994; Chance et al., 1993). Conversely, exogenous PMP22 gene expression aimed at alleviating the HNPP phenotype would be subject to the same tight window of PMP22 gene expression. In addition, gene therapy for Dejerine-Sottas syndrome and CMT1A cases due to (apparent gain-of-function) point mutations in PMP22 is encumbered by the fact that the exact biological function of the PMP22 gene product remains unknown. The development of an effective therapeutic regimen for Charcot-Marie-Tooth disease and related neuropathies, either through gene therapy or conventional drug design, requires a basic understanding of PMP22 physiology in a non-pathological setting (Roa and Lupski, 1993).
The development of molecular genetic techniques coupled with the availability of animal models have facilitated tremendous progress on the molecular genetics of inherited myelin disorders in recent years. To put it in perspective, Charcot-Marie-Tooth disease was first described in 1886 (Tooth, 1886; Charcot and Made, 1886) but it was not until 1992 that the PMP22 myelin gene was identified as the CMT1A candidate gene and subsequently confirmed (Matsunami et al., 1992; Patel et al., 1992; Roa et al., 1993a; Timmerman et al., 1992; Valentijn et al., 1992a, b). With the identification of a disease gene such as PMP22, mutations can be rapidly identified by screening multiple unrelated patients. This can be done in a relatively short time, and the PMP22 gene in hereditary peripheral neuropathies, as well as the PLP gene in Pelizaeus-Merzbacher disease and spastic paraplegia, provide examples wherein the number of disease-associated mutations in humans has quickly surpassed all the mutations in animal models (Table 1). This "catalogue'' of mutations enables preliminary structure-function correlations to be made in the absence of definitive protein structural data.
In summary, a combination of multidisciplinary approaches has enabled us to understand the molecular bases for Charcot-Marie-Tooth disease and other hereditary myelin disorders, or "myelinopathies," in man. The identification of the disease-causing genes has greatly increased our understanding of disease processes, delineated the concept of a "gene expression window" for a dosage-sensitive gene, and has immediately led to the development of molecular diagnostic tests. Moreover, this knowledge provides a clearer focus for multidisciplinary efforts towards elucidating the cascade of events beginning with a mutation in a gene, or increased dosage of a normal gene, ultimately leading to recognizable disease phenotypes.
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TABLE 1 Mutations associated with neurological phenotypes
| Gene | Disease | Mutation | References |
| Structural Gene Alterations: | |||
| PMP22 | CMT1A | Leu16Pro* | Valentijn et al., 1992a |
| PMP22 | CMT1A | Ser79Cys | Roa et al., 1993a |
| PMP22 | CMT1A | Thr118Met | Roa et al., 1993b |
| PMP22 | DSS | Met69Lys | Roa et al., 1993c |
| PMP22 | DSS | Ser72Leu | Roa et al., 1993c |
| PMP22 | HNPP | Ser7FS | Nicholson et al., 1994 |
| PMP22 | Trembler mouse | Gly150Asp | Suter et al., 1992a |
| PMP22 | TremblerJ mouse | Leu16Pro* | Suter et al., 1992b |
| Gene Dosage Alterations: | |||
| PMP22 | CMT1A | CMT1A dup | Lupski et al., 1991b |
| PMP22 | CMT1A | 17p dup | Lupski et al., 1992 Chance et al., 1992 Upadhyaya et al., 1993 Roa et al., 1993d |
| PMP22 | HNPP | HNPP del | Chance et al., 1993 |
| Structureal Gene Alterations: | |||
| PLP | PMD | Pro215Ser | Gencic et al., 1989 |
| PLP | PMD | Trp162Arg | Hudson et al., 1989 |
| PLP | PMD | Pro14Leu | Trofatter et al., 1989 |
| PLP | PMD | Tyr206Cys | Bridge et al., 1991 |
| PLP | PMD | Val218Phe1 | Pham-Dinh et al., 1991 |
| PLP | PMD | Thr155Ile | Pratt et al., 1991 |
| PLP | PMD | Asp202His | Doll et al., 1992 |
| PLP | PMD | Gly73Arg | Doll et al., 1992 |
| PLP | PMD | Leu223Pro | Strautnieks et al., 1992 |
| PLP | PMD | Thr181Pro | Strautnieks et al., 1992 |
| PLP | PMD | Gly220Cys | Iwaki et al., 1993 |
| PLP | PMD | Ser195Frameshift | Pham-Dinh et al., 1993 |
| PLP | PMD | Val165Glu | Pratt et al., 1993 |
| PLP | SPG | His139Tyr | Saugier-Veber et al., 1994 |
| PLP | SPG | Ile186Thr* | Kobayashi et al., 1994 |
| PLP | jimpy mouse | AG-GG splice site mutation (intron 4) | Nave et al., 1987a |
| PLP | jimpymsd mouse | Ala242Val | Gencic and Hudson, 1990 |
| PLP | rumpshaker mouse | Ile186Thr* | Schneider et al., 1992 |
| PLP | myelin-deficient rat | Thr74Pro | Boison and Stoffel, 1990 |
| PLP | shaking pup dog | His36Pro | Nadon et al., 1990 |
| Gene Dosage Alterations: | |||
| PLP | PMD | PLP deletion | Raskind et al., 1991 |
| PLP | PMD | PLP duplication | Cremers et al., 1987 Cremers et al., 1988[ Ellis and Malcolm, 1994 |
| PLP | PMD-like | PLP overexpressing transgenic mouse | Kagawa et al., 1994 Readhead et al., 1994 |
* Denotes identical mutation in human disease and mouse model
FIGURE 1 Proposed structural models for the integral membrane proteins PMP22 of peripheral nervous system myelin (Suter et al., 1992a), and PLP of central nervous system myelin (Popot et al., 1991). The PMP22 glycosylation site is indicated. Alternative splicing of the PLP gene yields the isoform DM20, which has an in-frame deletion of 35 amino acides dashed lines) at the intracellular loop region. The human neurological disorders associated with mutations in PMP22 and PLP genes are enclosed in boxes, and the associated animal models are listed below.
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