Human Molecular Genetics, 2000, Vol. 9, No. 6 987-992
© 2000 Oxford University Press
The proteolipid protein gene and myelin disorders in man and animal models
Applied Neurobiology Group, Glasgow University Veterinary School, Bearsden Road, Glasgow G61 1QH, UK and 1Clinical and Molecular Genetics Unit, Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UK
Received 7 January 2000; Accepted 9 February 2000.
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ABSTRACT |
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 TOP ABSTRACT MOLECULAR GENETICS OF PELIZAEUS...THE PLP GENE AND...MUTATIONS OF THE PLP...DISEASE EXPRESSION IN FEMALES:...ANIMAL MODELSTRANSGENIC ANIMALSREFERENCES |
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The two proteins, proteolipid protein and DM20, which are encoded by alternative transcripts from the proteolipid protein (PLP) gene, are major components of central nervous system myelin. In man, mutations of these proteins cause Pelizaeus–Merzbacher disease (PMD), an X-linked dysmyelinating neuropathy. The mutations found are very varied, ranging from deletions, loss-of-function and missense mutations to additional copies of the gene. This same range of known genetic defects has been observed in animal models with spontaneous and engineered Plp gene mutations. The relationship between genotype and phenotype is remarkably close in the animal models and the PMD cases, making them useful models for studying the mechanisms of PLP gene-related disease. As a result, it has become clear that the PLP gene plays a wider role in neural development in addition to its function as a structural component of myelin. It has also emerged that duplications of the PLP gene are the commonest mutation in PMD. Genetic disorders arising from a dosage effect may be more common than previously recognized. The study of the PLP gene in this rare disorder is, therefore, contributing both to our understanding of neural development and maintenance and to the mechanisms of human genetic disorders.
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MOLECULAR GENETICS OF PELIZAEUS–MERZBACHER DISEASE |
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TOPABSTRACTMOLECULAR GENETICS OF PELIZAEUS...THE PLP GENE AND...MUTATIONS OF THE PLP...DISEASE EXPRESSION IN FEMALES:...ANIMAL MODELSTRANSGENIC ANIMALSREFERENCES |
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Pelizaeus–Merzbacher disease (PMD) is an X-linked myelin disorder of the central nervous system (CNS) in which the affected males have very reduced white matter. The clinical severity varies, but common characteristics include flickering eyes, rigidity and physical and mental retardation. In the severest (connatal) cases of PMD, death may occur within months but in the milder syndrome of spastic paraplegia type 2 (SPG2), cases may have only spasticity of the legs. Following the mapping of PMD to the long arm of the X chromosome (Xq22) (1), the proteolipid protein (PLP) gene became an obvious, although previously unsuspected, positional can- didate gene. Point mutations were demonstrated in a number of families, firstly in PMD (2,3) and then in the much milder manifestation of SPG2 (4,5). However, no mutation could be detected in the majority of cases, even when there was clear X linkage (6). It was found that duplications of the PLP gene (7) are an additional cause of PMD. The duplications, which can be detected usefully by interphase fluorescence in situ hybridization (FISH) for diagnostic purposes, are the most common cause of the disease (8–10). This provides a parallel to the common duplications of the PMP-22 gene which are the most frequent cause of the peripheral nervous system demyelinating neuropathy Charcot–Marie–Tooth disease type 1a (11).
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THE PLP GENE AND ITS ALTERNATIVE TRANSCRIPTS |
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TOPABSTRACTMOLECULAR GENETICS OF PELIZAEUS...THE PLP GENE AND...MUTATIONS OF THE PLP...DISEASE EXPRESSION IN FEMALES:...ANIMAL MODELSTRANSGENIC ANIMALSREFERENCES |
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The gene encodes two membrane-bound proteins of the myelin sheath, PLP, the major isoform, and DM20. The DM20 protein isoform differs from PLP by an internal deletion of 35 amino acids resulting from an alternative splicing event using a splice donor site within exon 3. The PLP gene is highly conserved across species, being identical in man, mouse and rat at the amino acid level. Further alternative minor forms result from the splicing in of a newly discovered exon lying between the previous exons 1 and 2 in the mouse (12). Splice variants containing this exon have the potential to add a 12 amino acid leader sequence to both the PLP and DM20 proteins which can direct the protein away from its predominant position in the CNS myelin membrane. This is consistent with recent findings that PLP and DM20 are more widely expressed in other tissues, including the peripheral nervous system and CNS neurons. However, a comparison with the human genomic sequence has revealed no homologous section, making the functional significance unclear at present.
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MUTATIONS OF THE PLP GENE IN THE HUMAN POPULATION LEADING TO PMD |
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TOPABSTRACTMOLECULAR GENETICS OF PELIZAEUS...THE PLP GENE AND...MUTATIONS OF THE PLP...DISEASE EXPRESSION IN FEMALES:...ANIMAL MODELSTRANSGENIC ANIMALSREFERENCES |
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A remarkable range of mutations involving the PLP gene has been observed (13,14). Some broad genotype–phenotype correlations are emerging. Most commonly, a large but variable sized duplication occurs (8,10,15) giving rise to PMD at the milder end of the spectrum. There is preliminary evidence that occasionally triplication of the PLP gene may occur (7,16; E. Sistermans, personal communication) associated with particularly severe early-onset disease. Point mutations occur throughout the gene and are generally associated with severe disease (9,17) (amino acid substitutions are illustrated graphically in Fig. 1a). A point mutation (His139Tyr) within exon 3B of the gene, and therefore affecting PLP but not DM20, was detected in a family with SPG2 (4). An isoleucine to threonine change at residue 186 in exon 4 was found in a further family with SPG2. This mutation is identical to the mutation identified in the rumpshaker mouse model (18). Rumpshaker mice also show a ‘milder’ phenotype and have normal longevity and a full complement of morphologically normal oligodendrocytes. Complete loss of the gene (19) or a mutation leading to loss or almost complete truncation of the protein result in a milder clinical phenotype. Two examples of the latter are a splice mutation leading to a stop codon after only two amino acids (20) and a transition in the initiation codon of the PLP gene which caused the total absence of PLP gene products (21).
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DISEASE EXPRESSION IN FEMALES: IMPLICATIONS OF X INACTIVATION |
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TOPABSTRACTMOLECULAR GENETICS OF PELIZAEUS...THE PLP GENE AND...MUTATIONS OF THE PLP...DISEASE EXPRESSION IN FEMALES:...ANIMAL MODELSTRANSGENIC ANIMALSREFERENCES |
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PMD usually acts as a recessive X-linked disorder with females unaffected. However, some females present with apparent signs of the disease. No affected female has been found carrying the duplication, but a number of point mutations have been described (20,22) in manifesting females. These are notable in that they are associated with milder disease in the males and include a Trp143stop mutation (22) and the previously described truncation after two amino acids (17). These results are all explicable in terms of X inactivation. Females carrying the duplication have heavily skewed non-random patterns of X inactivation, in contrast to those carrying most point mutations (23) and, as expected, do not show symptoms. In carrier females with point mutations, in which half the cells express the mutant phenotype, the fate apparently depends on the severity of the mutation, with cells surviving when there is a milder mutation. The consequences of X inactivation are taken further forward in the study of the shaking pup mutation (24) (see below).
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ANIMAL MODELS |
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TOPABSTRACTMOLECULAR GENETICS OF PELIZAEUS...THE PLP GENE AND...MUTATIONS OF THE PLP...DISEASE EXPRESSION IN FEMALES:...ANIMAL MODELSTRANSGENIC ANIMALSREFERENCES |
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Spontaneous point mutations of the Plp gene have been described in the mouse [Plpjp (25), Plpjp-4j (26), Plpjp-rsh (18) and Plpjp-msd (27)], rat [Plpmd (28)], dog [Plpsh (29)] and rabbit [Plppt (30)]. Several of these mutations mirror genetic defects that have been identified in families with PMD [Plpjp (31), Plpjp-rsh (32) and Plpjp-msd (33)]. Excluding the jimpy mouse, these animals have missense mutations of the Plp gene causing single amino acid substitutions (represented graphically in Fig. 1b). The jimpy mouse has a point mutation within intron 4 that disrupts splicing and excludes exon 5 from the mature Plp gene transcripts, producing novel Plp gene products, all of which have a truncated C-terminus (25,34). The majority of these mutant animals, including the jimpy mouse, have severe neurological dysfunction due to the reduced ability of the CNS to form myelin (illustrated in Fig. 2) and are suitable models for severe forms of PMD (reviewed in refs 35–37). Clinical signs, including tremors and seizures, develop early and may lead to premature death. The CNS has a dramatically reduced number of myelin sheaths and the myelin that does form is ultrastructurally abnormal and occurs as solitary internodes (38,39). In the phenotypically severe mutants, there are reduced numbers of mature oligodendrocytes (38,40,41) because of an increased rate of apoptosis (40–43). These changes mirror the classic pathology seen in many severely affected cases of PMD. Three of these models, the rumpshaker mouse (44), the paralytic tremor rabbit (45) and the shaking pup (46), have less severe phenotypes and survive into adulthood. In the rumpshaker mouse and paralytic tremor rabbit, this reflects less dramatic dysmyelination; although the CNS of these animals remains hypomyelinated, reasonable numbers of myelin sheaths form and oligodendrocyte numbers are maintained (44,47). These mutants provide models for SPG2 and milder cases of PMD.
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TRANSGENIC ANIMALS |
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TOPABSTRACTMOLECULAR GENETICS OF PELIZAEUS...THE PLP GENE AND...MUTATIONS OF THE PLP...DISEASE EXPRESSION IN FEMALES:...ANIMAL MODELSTRANSGENIC ANIMALSREFERENCES |
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Transgenic animals harbouring additional copies of the Plp gene have been generated as models of PMD caused by PLP gene duplications. Two transgene constructs containing the structural Plp gene driven by varying lengths of 5' sequence have been used to generate three transgenic lines of mice with varying transgene copy numbers [#66 and #72 transgenic lines (48); 4e transgenic line (49)]. In addition, two lines of mice with targeted mutations of the Plp gene have functional null alleles (50,51) and have been used as models of PMD resulting from null mutations or deletions of the PLP gene. Table 1 details the transgene constructs and Table 2 the targeting events used to generate these experimental animals and related transgenic models.
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Studies on human tissue and in animal models have led to three mechanisms of disease in PMD being proposed: loss of function, gain of function and gene dosage effects. One popular theory has been the effect of loss of functional PLP gene products on myelination. Point mutations of the Plp gene in animal models lead to large reductions in the levels of PLP and DM20 proteins, and these mutated gene products may also be functionally inactive. To account for the lack of myelin and reduced oligodendrocyte numbers in these mutants, roles for the Plp gene products as vital structural components necessary for myelin assembly and as oligodendrocyte maturation and survival factors have been proposed. The loss of these putative roles may compromise oligodendrocyte function sufficiently to lead to dysmyelination. This theory, however, is challenged by the findings that the Plp gene knockout mouse (51) and mice carrying the targeted mutation described by Boison and Stoffel (50) do not develop classic signs of Plp gene-related disease. They show minimal or no early clinical phenotype and produce large volumes of myelin while maintaining normal oligodendrocyte numbers in the absence of PLP and DM20 proteins (51,52). Although these animals do have ultra- structurally abnormal myelin (51,53), they show that at least some of the features of PMD must result from mechanisms other than the loss of functional gene products (20).
To explain these anomalies, the gain-of-function hypothesis has been proposed. Gain-of-function mutations often can be identified by autosomal dominant inheritance patterns because mutated proteins dominate normal proteins expressed within the same cell. As the Plp gene is located on the X chromosome, this scenario does not arise in Plp gene-related disorders. Due to X inactivation, individual oligodendrocytes in females heterozygous for a mutation of the Plp gene express only one allele (either the mutated or the normal allele) and the ability of mutated gene products to dominate normal gene products cannot be assessed. However, in transgenic systems in which the jimpy and wild-type alleles are expressed in a single cell, the mutant allele appears dominant (54).
Mutated Plp gene products may have gain-of-function properties that prove deleterious to cellular function, e.g. disrupting protein trafficking in the oligodendrocyte. In some animal models with point mutations of the Plp gene, oligodendrocytes have distended rough endoplasmic reticulum (RER) and/or Golgi apparatus (38,55–57) mirroring changes identified frequently in cases of PMD. The mutated gene products can often be localized to the RER but not at the cell surface (42,58), suggesting that trafficking of PLP and DM20 proteins is abnormal. This may be due to conformational changes within the mutated proteins. However, in the rump- shaker mouse, reasonable levels of DM20 protein incorporate into the myelin sheath although only small amounts of PLP protein are produced and are partially retained within the oligodendrocyte cell body (59,60). Milder dysmyelination and oligodendrocyte survival in this mutant may relate to less severe disruption of protein trafficking. These mutated gene products may retain functional properties or may not acquire properties that prove deleterious to oligodendrocyte function. Although it is clear that trafficking of Plp gene products is altered in the spontaneous Plp gene mutants, the mechanism(s) that compromise oligodendrocyte function and lead to dysmyelination are still uncertain.
Structural changes are also reported in the RER and Golgi apparatus of some animals expressing transgenic copies of the Plp gene (48,49,61), suggesting that protein trafficking may also be disrupted by increased production of PLP gene products in cases of PLP gene duplications. However, alterations in gene dosage contributing to disease per se have been recognized and may have relevance in PMD. The high level of sequence identity in the 5'- flanking region of the Plp gene across mammalian species demonstrates the potential importance of tight regulatory control of Plp gene expression for normal function. In mice expressing transgenic copies of the Plp gene, a close correlation between phenotypic severity and transgene copy number is seen (49,61,62). A range of phenotypes develop, from severe dysmyelination (associated with high transgene copy number) to normal myelination followed later by demyelination (associated with low transgene copy number) (48,62). Transgenic mice also develop axonal swelling and degeneration (62), changes that occur less frequently in spontaneous Plp gene mutants (44,55,63–65). The Plp gene knockout mouse does not develop an early clinical phenotype but does have ultrastructurally abnormal myelin and develops a progressive axonopathy (52) with a distribution similar to that found in the aged transgenic mice (62). The similarities in pathology resulting from both decreased and increased Plp gene expression suggest that at least some aspects of disease, such as the development of axonal changes, may result from alterations in gene dosage.
Taken together, these findings suggest that several mechanisms contribute to disease. Ultrastructural abnormalities of myelin may reflect the loss of structural support by Plp gene products; oligodendrocyte death may result from disrupted protein trafficking; axonal pathology may reflect alterations in gene dosage.
Although the models described above provide a full range of genetic homologues for PMD, some phenotypic differences are seen. For example, the Plp gene knockout mouse does not develop the early clinical phenotype or severe peripheral neuropathy described in humans with similar genetic defects (20). These anomalies may reflect different roles for the Plp gene products or differences in compensatory mechanisms between species. However, the Plp gene knockout mouse may offer a better correlate for human disease than at first appears. Like the Plp gene knockout mouse, the CNS of humans with similar genetic defects appears well myelinated in adolescents but is severely hypomyelinated at post-mortem in older patients (20). The development of axonal pathology in the Plp gene knockout mouse has led to the re-evaluation of material from PMD cases. Preliminary results suggest that in a range of cases, including those resulting from functional null alleles of the PLP gene, axonopathies develop (I.R. Griffiths, personal communication). The early phenotype and later hypo- myelination of human cases with PLP gene-null alleles may reflect the progression of axonal changes with associated fibre degeneration.
Phenotypic differences between animals and humans, such as those described above, could result from different neurological requirements or from the differences in absolute compared with relative age between mouse and man. Other mechanisms, such as the role of modifying genes, may also affect phenotypic severity. For example, the rumpshaker mutation produces a severe phenotype when introduced into the C57BL/6 strain of mice (K.-A. Nave, personal com- munication), and phenotypic heterogeneity spontaneously developed and segregated within populations of myelin-deficient rats (63). Heterogeneity within families with PMD (reviewed in refs 17,66) and SPG2 (5,15,67) may also reflect the effects of modifying genes.
In summary, animal models have provided a unique opportunity to investigate the pathogenesis of PMD. Tissue sampling can be performed throughout all stages of disease progression, and transgenic strategies can be employed to provide additional models. In addition, and outside the range of this review, numerous in vitro systems have been used to address many of these issues. Many interesting points have been raised, but conclusive proof of disease pathogenesis remains elusive. Advances in transgenic and transplantation technology will enable many of these theories to be challenged directly in vivo, and existing models can be used to investigate modifying genes and compensatory mechanisms. Loss of functional gene products clearly plays some role in these disorders, but attention is turning towards other disease mechanisms.
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ACKNOWLEDGEMENTS |
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We gratefully acknowledge Prof. I.R. Griffiths for supplying the images used in Figure 2 and for proof reading this document. We would like to acknowledge the meeting ‘Workshop on Pelizaeus–Merzbacher Disease/X-linked Spastic Paraplegia Type 2’, NIH, October 1999, organized by Dr L.D. Hudson, that proved extremely useful in the preparation of this document. The authors are funded by Action Research (J.M.E.), the Douglas Hodges Charitable Trust (P.M.), the Multiple Sclerosis Society (D.A.Y.), the Wellcome Trust (S.M.) and CLIMB (S.M.).
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FOOTNOTES |
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+ To whom correspondence should be addressed. Tel: +44 141 330 5700; Fax: +44 141 942 7215; Email: d.yool@vet.gla.ac.uk
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REFERENCES |
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TOPABSTRACTMOLECULAR GENETICS OF PELIZAEUS...THE PLP GENE AND...MUTATIONS OF THE PLP...DISEASE EXPRESSION IN FEMALES:...ANIMAL MODELSTRANSGENIC ANIMALSREFERENCES |
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