Human Molecular Genetics, 2001, Vol. 10, No. 4 415-421
© 2001 Oxford University Press
A mutation in periaxin is responsible for CMT4F, an autosomal recessive form of Charcot–Marie–Tooth disease
1INSERM U289, 2Fédération de Neurologie, 3Consultation de Génétique Médicale, Hôpital de la Salpêtrière, 47 Boulevard de l’Hôpital, Paris, France, 4Department of Preclinical Veterinary Sciences, University of Edinburgh, UK, 5Unité de Génétique Médicale, Faculté de Médecine, Université Saint Joseph, Beirut, Lebanon and 6Laboratoire de Génétique Moléculaire, Institut de Biologie, Montpellier, France
Received 20 December 2000; Accepted 22 December 2000.
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ABSTRACT |
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Charcot–Marie–Tooth (CMT) disease is a heterogeneous group of inherited peripheral motor and sensory neuropathies characterized by chronic distal weakness with progressive muscular atrophy and sensory loss in the distal extremities. Inheritance can be autosomal dominant, X-linked or autosomal recessive (ARCMT). Recently, a locus responsible for a demyelinating form of ARCMT disease, named CMT4F, has been mapped on 19q13 in a large consanguineous Lebanese family. L- and S-periaxin are proteins of myelinating Schwann cells and homozygous periaxin-null mice display extensive demyelination of myelinated fibers in the peripheral nervous system, which suggests that the periaxin gene is a good candidate gene for an ARCMT disease. The human gene encoding the periaxins (PRX) was mapped to 19q13, in the CMT4F candidate interval. After characterizing the human PRX gene, we identified a nonsense R196X mutation in the Lebanese family which cosegregated with CMT. Histopathological and immunohistochemical analysis of a sural nerve biopsy of one patient revealed common features with the mouse mutant and the absence of L-periaxin from the myelin sheath. These data confirm the importance of the periaxin proteins to normal Schwann cell function and substantiate the utility of the periaxin-null mouse as a model of ARCMT disease.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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Charcot–Marie–Tooth (CMT) disease is the most common inherited peripheral neuropathy. It is generally characterized by progressive muscular atrophy and weakness with sensory loss in the distal extremities of the limbs (1). On the basis of clinical and electrophysiological criteria, CMT disease has been classified into two major groups: (i) CMT1, or demyelinating neuropathies; and (ii) CMT2, or axonal neuropathies (2). Various modes of inheritance are observed: dominant or recessive autosomal, or dominant X-linked. Over the last 10 years, increasing genetic data on the autosomal recessive forms of demyelinating CMT (ARCMT) have revealed the complexity and heterogeneity of this group. Although there is still some debate as to the most appropriate nomenclature, thus far demyelinating ARCMT has been defined as a new entity, CMT type 4. To date, eight loci have been implicated in CMT4 (3–10) and three genes have been identified: EGR2 (7), MTMR2 (11) and NDRG1 (12). One of these loci, named CMT4F, was mapped in an 8.5 cM interval on chromosome 19q13 in a large inbred Lebanese family (9).
Here, we have characterized the genomic structure of the human Periaxin gene and have mapped it to 19q13 into the CMT4F candidate region. Periaxin was first described as a protein expressed by myelinating Schwann cells of the developing mammalian peripheral nervous system (PNS) (13). As myelin sheaths mature, periaxin becomes predominantly localized at the abaxonal membrane which suggests that it might participate in the membrane–protein interactions that are required to stabilize the mature sheath (14). The identification of PDZ domains in the two periaxin isoforms (L- and S-periaxin) generated from the murine Prx gene by alternative intron retention implicated these modules in such protein–protein interactions (15). A role for the periaxins in the stabilization of the Schwann cell–axon unit was supported by the presence of extensive PNS demyelination in homozygous periaxin-null mice (16). Since the murine Prx gene maps to a region of chromosome 7 which is syntenic with human chromosome 19q (17), we felt that the Periaxin gene (PRX) might be a good candidate, both by function and position, for autosomal recessive CMT4F.
By sequencing PRX in a Lebanese patient, we found a homozygous nonsense mutation which cosegregated with CMT in the family. The premature stop codon leads to a truncated form of L-periaxin. By immunochemistry, we demonstrated that periaxin was undetectable in the sural nerve biopsy from a CMT4F patient. By light and electron microscopy, we observed that the morphology of the myelinated fibers in patients and periaxin-null mice was identical, supporting the observation that the mouse mutant is a convincing model for the human disease (17).
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RESULTS |
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Genomic structure and chromosomal localization of PRX
The human PRX gene was characterized based on its homology to the mouse Prx gene. We found that the entire PRX gene was contained in the bacterial artificial chromosome (BAC) CTC-492K19 and spanned
19.6 kb. By comparing the sequences of human genomic DNA, human expressed sequence tags (ESTs), mouse cDNA and the mouse gene (15), we showed that PRX, like the murine gene, is also divided into seven exons, the seventh being the largest with 4005 bp (Fig. 1). The initiation codon site is located in exon IV and, for the larger periaxin isoform, L-periaxin, the human gene encodes a 1461 amino acid protein, 70 amino acids longer than the mouse protein. Both proteins share 77.6% amino acid identity (Fig. 2). To study the alternative splicing of the PRX gene in human, we carried out RT–PCR analysis between exons VI and VII. We showed that two different products are amplified in human peripheral nerve as described in mouse (15): skipping intron 6 generates a 61 bp product whereas a 710 bp amplicon is observed when the intron is retained (Fig. 3). Moreover, we showed that the mRNA for both L- and S-PRX isoforms were co-expressed in human Schwann cells (Fig. 3).
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Two primers in intron 6 were designed to localize the PRX gene in the human genome using the GeneBridge 4 Radiation Hybrid DNA panel. The best radiation LOD scores (9.6 and 8.7) were obtained for two markers, D19S421 and D19S211, in an interval syntenic to the region of mouse chromosome 7 to which mouse Prx was previously mapped (17). Both markers localized to 19q13 into the CMT4F candidate region, a locus responsible for a demyelinating form of ARCMT that had been identified in a large inbred Lebanese family (9).
PRX mutation analysis
As the PRX gene became, both by function and position, an attractive candidate gene for CMT4F, we designed primers to specifically amplify and sequence the four coding exons (IV–VII) and their flanking splice sites and the intron 6 in patients from the Lebanese CMT family. We identified a homozygous C
T transition at position 860 which leads to a premature stop codon at the beginning of exon VII (R196X) (Fig. 4). This nonsense mutation truncates the C-terminus of L-periaxin by 1266 amino acids and leads to the absence of a large repeat-rich domain and a C-terminal acidic domain, the functions of which are not yet fully characterized (13). It also abolishes a recognition site for RsaI, which was used to confirm the segregation of the mutation with the disease (Fig. 4). RsaI restriction analysis of 100 chromosomes from Lebanese controls confirmed that the R196X mutation was specific to the affected patients.
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Immunochemical and light microscopy analysis
The genetic evidence for a mutation in the PRX gene was supported by comparative immunocytochemical analyses of control and patient sural nerve biopsies. Although the number of myelinated fibers was severely reduced in the proband nerve, it was possible to discern a restricted number of small-diameter fibers that were positive for the myelin constituent myelin basic protein (MBP) (Fig. 5A). MBP was also detected in the myelin sheaths around both large- and small-diameter fibers in control nerve (Fig. 5C). Crucially, periaxin was undetectable by immunochemistry in the affected nerve using an antibody which recognizes L-periaxin (Fig. 5B) whereas it was readily demonstrable in the control sample (Fig. 5D). In support of the view that the deficit was unique to periaxin, myelin protein P0, a characteristic component of PNS myelin, colocalized with MBP in the myelin sheaths of both control and affected nerves (data not shown).
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The dearth of myelinated axons in the CMT4F patient’s sural nerve was confirmed by light microscopy of plastic sections (Fig. 6A). A striking feature of the CMT4F nerve was the incidence of both ‘onion bulb’ structures (Fig. 6B) and hypermyelinated outfoldings with associated axonal compression (Fig. 6C). The former represent supernumerary Schwann cells associated with abortive attempts to remyelinate demyelinated nerves. Significantly, the presence of excess folded myelin in the peripheral nerves of periaxin-null mice (Fig. 6D) further supports the view that the mouse mutant is a convincing model for the human disease (16).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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Following EGR2 (7), MTMR2 (11) and NDRG1 (12), we have identified PRX as the fourth gene implicated in ARCMT. Cosegregation of the R196X mutation with the disease, its absence in the general population from which the family originated and the resulting truncation in L-periaxin provided the molecular clue for the pathogenesis of CMT4F. The specific deficit in L-periaxin in affected nerves compared with the myelin proteins MBP and P0 confirmed the deleterious effect of the mutation at the cellular level. Although, in principle, it is possible that the S-periaxin protein is still expressed, since the mutation is downstream of the retained intron 6 that encodes the C-terminus of this shorter isoform in the murine gene (15), the absence of L-periaxin appears to be sufficient to lead to demyelination. In adult mice, L-periaxin is concentrated in the abaxonal myelin lamella whereas S-periaxin is distributed throughout the cytoplasm (15). Therefore, it is very likely that each of these proteins do have distinct functions. Hence, further study of the relative involvement of these two periaxin isoforms in the assembly and stabilization of mouse PNS myelin is likely to shed further light into their particular roles in the pathogenesis of CMT4F.
The similarities in the histopathology of peripheral nerve from the CMT4F patient compared with that of the periaxin-null mouse were striking. Supernumerary Schwann cells surrounding thinly myelinated or naked axons forming the so-called ‘onion-bulb’ structures were commonly found in the patient together with hypermyelinated regions of the nerve in which the myelin was extensively folded. The origin of this excess folded myelin is obscure but its accumulation is a likely forerunner of massive demyelination. The occurrence of both histopathological hallmarks of different forms of CMT in the same condition is uncommon. Hence, it is significant that the peripheral nerves of periaxin-null mice have a very similar morphology (16), which further supports the view that this mouse model will lead to a better understanding of the human disease.
A distinctive and early feature of the periaxin-null mouse phenotype is the presence of severe neuropathic pain behavior characterized by mechanical allodynia and thermal hyperalgesia (16). Therefore, it is of great interest that, in addition to the motor deficit common to most forms of CMT, CMT4F patients display a variety of distal sensory abnormalities, including pain in both the upper and lower extremities (9). In the mouse mutant it has been shown that this neuropathic pain can be abrogated by intrathecal administration of an NMDA antagonist, which suggests that there have been plastic changes in the spinal processing sensory input from the extremities (17). Consequently the therapeutic application of such drugs that are available for the treatment of such neuropathic pain may provide some amelioration for CMT4F patients. Furthermore, since the origin of neuropathic pain as a result of nerve damage in general, and in response to demyelination in particular, is poorly understood, further study of the periaxin-null mouse is likely to provide new insights that will be of therapeutic benefit in a variety of demyelinating conditions, particularly in CMT4F.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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Patients
Fourteen members (three parents, three non-affected members and eight affected patients) of a Shiite Muslim family from the south of Lebanon were investigated, and the clinical data have been reported elsewhere (9). All patients presented with a demyelinating neuropathy with no detectable nerve conduction velocities.
Determination of the genomic structure of Periaxin
Murine exonic primers were used to amplify human Periaxin sequences from human cDNA. Further exonic sequence was obtained by PCR using specific primers from cDNA, genomic DNA and a human plasmid artificial chromosome library (Human Genome Mapping Project, Cambridge). We then compared our sequence with the BAC sequence CTC-492K19 (GenBank accession no. AC010271), five human ESTs (AA984421, AW590908, AI637869, AW105547 and AW337783) and the published mouse periaxin cDNA (GenBank accession no. GI9506998).
Human radiation hybrid mapping of PRX
To determine the location of the human PRX gene, the GeneBridge 4 radiation hybrid mapping panel (18) was typed by PCR amplification with human PRX-specific primers. PCR primers 5'-GATCCGGTCTCTGCGCCGTGA-3' and 5'-CACTTCTTGCCTGTCATTTC-3' were designed specifically to amplify a sequence of 440 bp in intron 6 of the human PRX gene. Scores of locations were obtained by submitting the typing data to the publicly available RHmapper at the Sanger Center.
RT–PCR
Approximately 2 µg of total RNA was reverse transcribed using the Thermoscript RT–PCR system from Gibco BRL. This reaction (2 µl) was used for PCR performed at an annealing temperature of 56°C with gene-specific primers for PRX and GAPD (encoding glyceraldehyde-3 phosphate dehydrogenase). The PRX expression was studied after two rounds of PCR. An aliquot (2 µl) of the first PCR performed with the two primers 5'-GTCTGGCTACGAGATCAAG-3' and 5'-CCATCTTCTTCTTCTTCAC-3' was used for a nested-PCR with an inner reverse primer 5'-GGACAGACTCTGGATGTT-3'. For GAPD, the forward (5'-GCGAGATCCCTCCAAAATCA-3') and reverse (5'-TGTCATACTTCTCATGGTTCACACC-3') primers were designed on both sides of intron 4 to assess for the absence of DNA contamination.
Mutation screening
Primer sequences for exons of PRX are available on request. Exon 7 (4005 bp) was amplified in 10 overlapping PCR fragments. The PCR products were purified using QiaQuick PCR Purification kit (Qiagen) and sequenced by BigDye terminator chemistry (Perkin-Elmer) on an ABI377 (Perkin-Elmer).
RsaI analysis
The PCR product of the first fragment of exon 7 was subjected to RsaI digestion (3 h at 42°C) followed by agarose (2%) gel analysis.
Microscopy
Sections (5 µm) of formalin-fixed sural nerve biopsies embedded in paraffin were collected on 3-aminopropyltriethoxysilane-subbed slides. The sections were dewaxed, rehydrated and microwaved in 0.1 M citrate buffer (10 min), following which they were fixed in paraformaldehyde (4%) (19). Double-label immunofluorescence for L-periaxin and MBP was then carried out as described previously (15). Light microscopy of toluidine-stained plastic sections (1 µm) and electron microscopy of immersion-fixed sural nerve biopsies was as described (16).
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ACKNOWLEDGEMENTS |
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A.W. thanks Dr Stewart Gillespie and Prof. Jeanne Bell (both University of Edinburgh) for help and advice. Dr B. Zalc is particularly thanked for facilitating the collaboration between the Edinburgh and Paris groups. We are grateful to the members of the family who were always very cooperative. P.J.B. thanks the Wellcome Trust for financial support and the University of Edinburgh for a Fellowship for A.W. V.D. thanks the Université Saint-Joseph for financially supporting her work. This study was funded by the Association pour le Developpement de la Recherche sur les Maladies Neurologiques et Psychiatriques (ADRMGNP) and by the Association Française contre les Myopathies (AFM). A.G. is supported financially by the AFM. A part of the technical work performed in Group 2 was supported by grants from the Jerome Lejeune Foundation.
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FOOTNOTES |
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+ These authors contributed equally to this work
§ To whom correspondence should be addressed. Tel: +33 1 42 16 22 07; Fax: +33 1 44 24 36 58; Email: guilbot@ccr.jussieu.fr
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REFERENCES |
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