Original Article
Charcot-Marie-Tooth Disease Type 1A -- Association with a Spontaneous Point Mutation in the PMP22 Gene
N Engl J Med 1993; 329:96-101July 8, 1993
- Abstract
Background
Charcot-Marie-Tooth disease (CMT) is the most common inherited peripheral neuropathy. CMT type 1A is associated with a 1.5-megabase (Mb) DNA duplication in region p11.2-p12 of chromosome 17 in most patients. An increased dosage of a gene within the duplicated segment appears to cause the disease. The PMP22 gene, which encodes a myelin protein, has been mapped within the duplication and proposed as a candidate gene for CMT type 1A.
Methods
We analyzed DNA samples from a cohort of 32 unrelated patients with CMT type 1 who did not have the 1.5-Mb tandem duplication in 17p11.2-p12 for mutations within the PMP22 coding region. Molecular techniques included the polymerase chain reaction (PCR), heteroduplex analysis to detect point mutations, and direct nucleotide-sequence determination of amplified PCR products.
Results
A 10-year-old boy was identified with a point mutation in PMP22, which resulted in the substitution of cysteine for serine in a putative transmembrane domain of PMP22. Analysis of family members revealed that the PMP22 point mutation arose spontaneously and segregated with the CMT type 1 phenotype in an autosomal dominant pattern. The patients with the PMP22 point mutation had clinical and electrophysiologic phenotypes that were similar to those of patients with the 1.5-Mb duplication.
Conclusions
The PMP22 gene has a causative role in CMT type 1. Either a point mutation in PMP22 or a duplication of the region including the PMP22 gene can result in the disease phenotype.
Media in This Article
Figure 1
PCR Amplification and Heteroduplex Analysis of the PMP22 Coding Region.Figure 2
Pedigree of a Family (HOU226) with CMT Type 1.Article Activity
- Article
Charcot-Marie-Tooth disease (CMT)1,2 is the most common inherited peripheral neuropathy, with a frequency of 1 in 2500,3 and is one of the most prevalent autosomal dominant diseases4. It is a clinically heterogeneous disorder of the peripheral nerves characterized by slowly progressive atrophy of the distal muscles, predominantly those innervated by the peroneal nerve4,5. Progressive weakness of varying intensity and atrophy of the muscles of the feet, hands, and legs, leading to pes cavus deformity, clawhand, and stork-leg appearance, usually begin in the second or third decade of life4,5. Enlarged greater auricular nerves may be visible in the neck, and enlarged ulnar and peroneal nerves may be palpated in some patients. Cranial nerves are rarely involved. Some patients also have decreased responses to pain in a “stocking” distribution4. Neuropathological features include hypertrophic neuropathy with “onion bulb” formation6. Two major types of CMT can be distinguished on the basis of electrophysiologic studies: type 1 is characterized by uniformly slowed nerve conduction velocity in motor nerves (Garcia CA, et al.: unpublished data) and absent stretch reflexes, indicating a demyelinating disorder that is probably due to an intrinsic Schwann-cell defect, whereas type 2, the neuronal form, is characterized by normal or near-normal nerve conduction velocity and normal stretch reflexes4,5.
CMT is genetically heterogeneous, with X-linked, autosomal dominant, autosomal recessive, and sporadic cases reported5,7. The most common form, type 1A, has an autosomal dominant pattern of inheritance, with linkage of the disease locus to DNA markers on chromosome 17p5,8. In the majority of patients with CMT type 1A, a DNA duplication of 1.5 megabases (Mb) in 17p11.2-p12 has been identified,9-16 which apparently leads to a gene-dosage effect17-20. The duplication was shown to arise as a spontaneous mutation,10 and accounted for 90 percent of the sporadic cases of CMT type 1A in one study11.
The proposed candidate gene for CMT type 1A, PMP22, which encodes a peripheral myelin protein with an apparent molecular weight of 22,000, maps within the area of duplication,21-24 and demonstrates high levels of tissue-specific expression in the peripheral nervous system21,25. Furthermore, the myelin-deficient trembler (autosomal dominant) and tremblerj (semidominant) mouse models of CMT type 1 contain point mutations in murine Pmp2226,27. These combined findings led to the hypothesis that CMT type 1A may result from alternative mechanisms of gene duplication or a point mutation of PMP22.
This study sought to substantiate the role of the candidate gene PMP22 in the disease process of CMT type 1. The PMP22 gene was analyzed for mutations in 32 unrelated patients who had decreased motornerve conduction velocities (CMT type 1) but who did not have the CMT type 1A duplication.
Methods
Evaluation of Patients
More than 100 unrelated patients with CMT underwent clinical and electrophysiologic evaluation. Studies of motor-nerve conduction velocity were performed with an electromyograph (model TD20, TECA, White Plains, N.Y.). Uniformly decreased motor-nerve conduction velocity was the electrophysiologic criterion for the diagnosis of CMT type 1. Conduction velocities were tested in the median and ulnar nerves, and in the peroneal nerve in some patients. The reductions in motor-nerve conduction velocities in patients with CMT type 1 were nearly identical in proximal and distal nerve segments and in bilateral nerves tested (Garcia CA, et al.: unpublished data).
Molecular analyses with several independent methods9 identified 32 unrelated patients with CMT type 1 but without the type 1A duplication (Wise CA, et al.: unpublished data) who were further analyzed for a mutation in the coding region of the PMP22 gene. A PMP22 point mutation was identified in one patient (Subject 7), who presented at 10 years of age with clinical symptoms of atrophy and weakness of the leg muscles, absent deep-tendon reflexes, and pes cavus. Motor-nerve conduction velocities were severely reduced: 9.7 and 9.8 m per second in the median and ulnar nerves, respectively. An analysis of family members revealed three with CMT type 1. Subject 6 presented with weakness of the intrinsic hand muscles in addition to the clinical findings present in his brother, Subject 7, and had motor-nerve conduction velocities of 9.0 and 12.0 m per second in the median and ulnar nerves, respectively. Subject 4 had clinical symptoms similar to those of his son, Subject 7, and nerve conduction velocities of 17.3 and 25.5 m per second in the median and ulnar nerves. The nerve conduction velocities in these patients with the PMP22 point mutation were close to or within the range observed in patients with the CMT type 1A duplication (10.4 to 42.0 m per second), but appear to lie at the lower end of the distribution28. Other family members had no clinical symptoms of CMT type 1, and those evaluated electrophysiologically had normal nerve conduction velocities (>50 m per second) in the median and ulnar nerves.
Molecular Analysis
The coding region of the PMP22 gene was amplified by the polymerase chain reaction (PCR) with the use of 300 ng of genomic DNA and 1.0 micromole primers in a volume of 50 microliters. Figure 1AFigure 1
PCR Amplification and Heteroduplex Analysis of the PMP22 Coding Region. shows the sequences of primer sets 1, 2, 3, and 4 that were used to amplify individual coding exons of PMP22. PCR conditions for primer sets 1, 3, and 4 were as follows: initial denaturation at 94 °C for 2.5 minutes, followed by 35 cycles consisting of denaturation at 94 °C for 1 minute, annealing at 60 °C for 1 minute, and extension at 72 °C for 1 minute, and a final cycle of extension at 72 °C for 7 minutes. An annealing temperature of 55 °C was used for primer set 2.For the analysis of heteroduplexes, 5 microliters each of PCR products derived from the individual family members and a nonpatient control was mixed, denatured at 95 °C for five minutes, and cooled to 35 °C. A negative control (10 microliters of control PCR product) was always included29. Loading dye was added (2 microliters), and the samples were loaded on a 1.0-mm-thick gel measuring 21 by 40 cm (Bio-Rad, Richmond, Calif.) with mutation detection enhancement acrylamide (A.T. Biochem, Malvern, Pa.). The bands were visualized with ethidium bromide according to the manufacturer's instructions.
Templates for the direct determination of the nucleotide sequence of biotinylated PCR products were generated by two rounds of PCR amplification. The first round was performed as described for each exon, and a second round (15 cycles) used 0.2 microliter of the first-round PCR product and 0.1 micromole primers, with one primer biotinylated at the 5' end. The templates were isolated on streptavidin beads by combining 20 microliters of PCR product with 33.4 microliters of Dynabeads (Dynal, Oslo, Norway) according to the manufacturer's instructions. The beads were resuspended in 20 microliters of TE buffer (10 mM TRIS-HCl, pH 7.5, 1 mM EDTA), and 7 microliters was used in dideoxy sequencing reactions with the Sequenase 2.0 kit (U.S. Biochemical, Cleveland) with use of35S-labeled deoxyadenosine triphosphate.
Paternity Testing
Paternity testing was performed by Southern blot analysis of DNA from Subjects 1, 2, 3, and 4 with use of single-locus probes D2S44, D4S139, D14S13, and D16S85 that provided a combined average power of exclusion of 99.93 percent.
Results
To identify patients with CMT type 1 who did not have the type 1A duplication, a cohort of unrelated patients with CMT type 1 was screened for the presence of the 1.5-Mb duplication in 17p11.2-p12 by several independent methods: pulsed-field gel electrophoresis to detect the 500-kb SacII junction fragment specific to the duplication, Southern blot analysis to examine differences in the dosage of polymorphic alleles detected by probes mapping within the duplication, and analysis of polymorphic RM11-GT dinucleotide repeat alleles (three alleles in the presence of the duplication) as described previously9. Screening of more than 100 patients with CMT revealed 32 apparently unrelated patients with CMT type 1 who did not have the CMT type 1A duplication (Wise CA, et al.: unpublished data).
Samples of DNA from these 32 unrelated patients were analyzed for mutations within the coding region of the CMT type 1 candidate gene PMP22. Studies of gene structure revealed that the PMP22 coding region includes four exons (unpublished data), and flanking primers were designed for PCR amplification of individual exons from genomic DNA (Figure 1A). The corresponding PCR products from the 32 unrelated patients were screened for mutations by heteroduplex analysis, wherein PCR products from patients and controls were combined to form duplexes, and base mismatches were detected by the presence of an additional heteroduplex band on high-resolution acrylamide gels29. One patient, Subject 7, was identified as having an apparent base mismatch in coding exon 3 (Figure 1B). Heteroduplex analysis of DNA from family members showed that a mutation in the third coding exon of PMP22 segregated with CMT type 1 (Subjects 4, 6, and 7) (Figure 1B and Figure 2Figure 2
Pedigree of a Family (HOU226) with CMT Type 1.). Heteroduplex analysis of exon 3 in 108 unrelated and unaffected control subjects revealed no apparent mismatch, indicating that the PMP22 mutation detected in the studied family is specific to CMT type 1 and is not a common polymorphism. Furthermore, Subject 4, whose parents were unaffected, had new-onset CMT type 1, which arose simultaneously with an apparently spontaneous mutation in PMP22. A tightly linked marker, RM11-GT,9 mapping within 50 kb of PMP22,12 was used to establish the paternal origin of this apparently new mutation (Figure 2). The results of DNA typing were consistent with paternity, with a probability of 99.98 percent. The clinical onset of CMT type 1 in the pedigree was therefore associated with an apparently spontaneous point mutation of paternal origin in PMP22.The DNA sequence of PCR products from individual family members was determined. This process identified a C-to-G transversion, resulting in a missense point mutation in the PMP22 coding region. Figure 3Figure 3
Sequence Determination of the PMP22 Mutation. shows the DNA sequence corresponding to the third coding exon of key family members (Subjects 1 and 4). The mutant and wild-type alleles were identified in heterozygous Subject 4, whereas only the wild-type allele was seen in his unaffected father (Subject 1). The same point mutation was detected in Subjects 4, 6, and 7, but was absent in unaffected family members (Subjects 1 and 2) (Figure 3). These data on DNA sequences, together with the verification that Subject 1, who was unaffected, was the father of Subject 4, who was affected, confirmed the spontaneous origin of this PMP22 mutation associated with CMT type 1. Determination of the sequence of four coding exons of Subject 4 did not identify any additional mutations (data not shown). The C-to-G point mutation corresponds to the substitution of cysteine for serine in the 79th codon (S79C) of PMP22 (Figure 3). This substitution occurs in the second putative transmembrane domain of PMP22 (Figure 4Figure 4
Point Mutations in PMP22 Homologues Affecting the Well-Conserved Putative Transmembrane Domains of PMP22.).Discussion
The identification of a spontaneous point mutation in the PMP22 gene that arises simultaneously with CMT type 1 and segregates with the disease phenotype in one family provides proof of the direct role of the PMP22 candidate gene in the disease process of CMT type 1A. This finding clearly demonstrates that two alternative mechanisms -- a point mutation in PMP22 and DNA duplication of a 1.5-Mb region on 17p11.2-p12 that includes PMP22 -- can give rise to the same disease phenotype. The overall similarity of the clinical and electrophysiologic findings in patients with CMT type 1A who have either the DNA duplication or the PMP22 point mutation means that molecular analysis is the only definitive way to distinguish between the two classes of patients.
Although the stably inherited DNA duplication31 is found in the majority of patients and families with CMT,6,9-17 approximately 30 percent of the patients we studied with slowed nerve conduction velocities did not have the duplication (Wise CA, et al.: unpublished data). The low frequency of mutation of the PMP22 gene observed among the 32 patients with CMT type 1 but without the duplication may be explained by (1) the absence of linkage data, which leaves open the possibility that some of these patients may have mutations at other genetic loci not on chromosome 17p5,7,32; (2) the analysis of only the coding region and not the regulatory regions of PMP22; and (3) possible limits in the ability of heteroduplex analysis to detect mutations.
The mechanism by which the CMT type 1A duplication causes the disease is best explained by the gene-dosage hypothesis, whereby the duplication of a CMT gene leads to increased levels of the gene product and ultimately results in the disease phenotype9,17,18. Several groups have proposed PMP22 as a dosage-sensitive CMT type 1A candidate gene21-24. In support of this hypothesis, recent evidence appears to rule out the loss of gene function or decreased levels of gene product as the basis for CMT type 1A. It was demonstrated that DNA deletion of a 1.5-Mb region on 17p11.2-p12, which includes PMP22, is associated with hereditary neuropathy with liability to pressure palsies (HNPP)33. In contrast to CMT type 1A, HNPP (also called “bulb diggers' palsy”) is characterized by pressure-induced palsies that remit gradually and by sensory- and motor-nerve conduction velocities that are normal to mildly reduced33,34. The alternative model of gene interruption at the junction of the CMT type 1A duplication is also unlikely to be the cause of the disease, since we demonstrated that a patient with 17p trisomy and a more extensive duplication of DNA had decreased motor-nerve conduction velocities characteristic of CMT type 118. Three additional patients with 17p trisomy and different cytogenetic breakpoints have been found to have reduced nerve conduction velocities, lending further support to the gene-dosage model19,20 (and unpublished data). The collective data are consistent with the hypothesis that increased expression of the peripheral-nerve-specific PMP22 gene causes the clinical and electrophysiologic phenotype of CMT type 118-24.
Point mutations causing amino acid substitutions in integral membrane proteins have been documented to cause autosomal dominant diseases, which now include CMT. In hyperkalemic periodic paralysis, missense mutations affecting transmembrane domains of the SCN4A skeletal-muscle sodium-channel gene product were identified, which presumably alter channel properties and result in disease35,36. The related disorder paramyotonia congenita is associated with different point mutations in SCN4A37,38. In autosomal dominant retinitis pigmentosa, individual point mutations collectively affect every transmembrane domain of rhodopsin39. These rhodopsin missense mutations segregate in an autosomal dominant manner,39 in contrast to the null mutations that are associated with autosomal recessive retinitis pigmentosa40. The PMP22 point mutation described here leads to a serine-to-cysteine substitution (S79C) in the fourth putative transmembrane domain of the integral membrane protein PMP2241 (Figure 4). This S79C substitution could alter protein structure and function through aberrant disulfide linkage. The previously identified point mutations in the murine Pmp22 gene of the trembler (G150D)26 and tremblerj (L16P)27 mouse models of CMT type 1 are located in evolutionarily conserved putative transmembrane domains21 (Figure 4). We proposed on the basis of its structure that PMP22 could function as a pore or channel protein or have a part in membrane adhesion21,25-27. Both hypotheses could accommodate the pathophysiologic mechanisms resulting from either PMP22 point mutation or 1.5-Mb duplication including the PMP22 gene.
To explain how a duplication encompassing PMP22 or a point mutation of PMP22 could result in CMT type 1A, we hypothesize that either mechanism could disrupt the sensitive macromolecular stoichiometry of the peripheral-nerve membrane. The PMP22 point mutation may constitute a dominant gain-of-function allele, leading to increased or altered function of PMP22, which could presumably mimic the effect of an increased level of gene product resulting from duplication. The involvement of these two mutational mechanisms was also suggested in autosomal dominant retinitis pigmentosa, wherein transgenic mice carrying a human rhodopsin mutation (P23H), as well as mice overexpressing the normal human rhodopsin transgene, had retinal photoreceptor degeneration42. On the other hand, the PMP22 point mutation could result in a dominant negative allele. In such a case, the mutation may theoretically lead to the inactivation of a multimeric protein complex, as postulated previously for the CLC-1 skeletal-muscle chloride-channel gene implicated in myotonia congenita43. The elucidation of the biologic function of PMP22 is critical to the unraveling of the exact mechanisms by which the gene duplication and point mutation of PMP22 lead to the same clinical and electrophysiologic phenotype. Understanding the basic pathophysiology may lead to therapies for CMT and other inherited peripheral neuropathies.
Note added in proof: Since this paper was submitted, another report was published that described a PMP22 point mutation in a family with nonduplication CMT type 1A44.
Supported by grants from the National Institute for Neurological Disorders and Stroke (NINDS) and the Muscular Dystrophy Association (to Drs. Patel and Lupski) and from the American Paralysis Association and NINDS (to Dr. Shooter). Dr. Suter is the recipient of a postdoctoral fellowship from the Swiss National Science Foundation and the Swiss Academy of Medical Sciences. Dr. Roa is a postdoctoral fellow of the Muscular Dystrophy Association. Dr. Lupski acknowledges support from the Pew Scholars Program in Biomedical Sciences.
We are indebted to the patients and their families for their continued cooperation and collaboration in our studies, to R. Fenwick and H. Hammond of the Baylor DNA diagnostic laboratory for assistance with DNA paternity testing, and to Drs. N. Abbas, A. Ballabio, A. Beaudet, and H. Bellen for their critical reviews.
Source Information
From the Institute for Molecular Genetics (B.B.R., D.A.K., C.A.W., P.I.P., J.R.L.), Human Genome Center (P.I.P., J.R.L.), and Department of Pediatrics (J.R.L.), Baylor College of Medicine, Houston; the Departments of Neurology (C.A.G., J.M.) and Pathology (C.A.G.), Louisiana State University School of Medicine, New Orleans; the Departments of Neurobiology (U.S., A.A.W., G.J.S., E.M.S.) and Neuropathology (G.J.S.), Stanford University School of Medicine, Stanford, Calif.; and the Department of Cell Biology, Swiss Federal Institute of Technology, ETH Honggerberg Zurich, Switzerland (U.S.).
Address reprint requests to Dr. Lupski at the Institute for Molecular Genetics, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX 77030-3498.
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