Alternative titles; symbols
HGNC Approved Gene Symbol: PMP2
Cytogenetic location: 8q21.13 Genomic coordinates (GRCh38): 8:81,440,326-81,447,439 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 8q21.13 | Charcot-Marie-Tooth disease, demyelinating, type 1G | 618279 | Autosomal dominant | 3 |
The PMP2 gene encodes a peripheral myelin protein important for lipid dynamics and myelin membrane stability. It is predominantly expressed in Schwann cells (summary by Hong et al., 2016 and Gonzaga-Jauregui et al., 2015).
Myelin is a multilamellar compacted membrane structure that surrounds and insulates axons, facilitating the conduction of nerve impulses. It is composed predominantly of lipids, with proteins accounting for about 30% of its net weight. Schwann cells are responsible for myelin formation in the peripheral nervous system. Peripheral myelin protein-2 (PMP2), a small basic protein, is one of the major proteins of peripheral myelin and appears to be related to the transport of fatty acids or the metabolism of myelin lipids. Hayasaka et al. (1991) noted that PMP2 (which they also called myelin P2 protein, MP2) was shown to have lipid-binding activity. Thus, MP2 protein may have an important role in the organization of compact myelin.
Hayasaka et al. (1991) isolated a full-length cDNA of MP2 protein of peripheral myelin from a cDNA library of human fetus spinal cord. It was found to contain a 393-bp open reading frame encoding a polypeptide of 131 residues. The deduced amino acid sequence is highly homologous to myelin P2 protein from other species.
Hayasaka et al. (1993) cloned the genomic PMP2 sequence, which is about 8 kb long and consists of 4 exons. All exon-intron junction sequences conform to the GT/AG rule. The 5-prime flanking region of the gene has a TA-rich element (TATA-like box) and a single defined transcription initiation site as detected by the primer extension method.
By spot-blot hybridization (FISH) of flow-sorted human chromosomes and fluorescence in situ hybridization, Hayasaka et al. (1993) mapped the PMP2 gene to 8q21.3-q22.1. This is the same region as that in which the autosomal recessive form of Charcot-Marie-Tooth peroneal muscular atrophy (CMT4A; 214400) has been mapped. Thus, the PMP2 gene was a prime candidate for the site of the mutation in that disorder.
Narayanan et al. (1994) reported the partial structure of the PMP2 gene. Using a panel of human/hamster somatic cell hybrids and by FISH, they localized the gene to 8q21. Ben Othmane et al. (1995) created a 7-Mb YAC contig spanning the region of 8q13-q21 to which the CMT4A gene was mapped. This contig was used to map 9 additional microsatellites and 6 STSs to this region; subsequent haplotype analysis narrowed the CMT4A flanking interval to less than 1 cM. Using SSCP and the physical map, they could demonstrate that the PMP2 gene is not the defect in CMT4A.
In a father and son (family BAB1468) with demyelinating Charcot-Marie-Tooth disease, type 1G (CMT1G; 618279), Gonzaga-Jauregui et al. (2015) identified a heterozygous missense mutation in the PMP2 gene (I43N; 170715.0001). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Functional studies of the variant and studies of patient cells were not performed, but studies in zebrafish suggested that it was pathogenic (see ANIMAL MODEL). These authors suggested a dominant-negative effect. The proband was part of a cohort of 37 unrelated families with a similar phenotype who underwent whole-exome sequencing.
In 3 affected members of a Korean family (family FC183) with CMT1G, Hong et al. (2016) identified a heterozygous I43N substitution in the PMP2 gene. The mutation, which was found by whole-exome sequencing, segregated with the disorder in the family. Studies of patient cells were not performed, but transgenic mice with the I43N mutation developed a peripheral neuropathy similar to that found in the patients (see ANIMAL MODEL).
In affected members of 2 unrelated families with CMT1G, Motley et al. (2016) identified missense mutations in the PMP2 gene (I52T, 170715.0002 and T51P, 170715.0003). Functional studies of the variant and studies of patient cells were not performed, but Motley et al. (2016) suggested that the mutations may result in aberrant transport of fatty acids and possibly result in a toxic gain of function.
Gonzaga-Jauregui et al. (2015) found that morpholino knockdown of either of the 2 zebrafish pmp2 orthologs caused a motor neuron phenotype including failure of the motor neuron axons to extend from the notochord, as well as pathfinding errors where the axons failed to innervate the myotomes appropriately. Overexpression of human wildtype PMP2 induced a similar phenotype, suggesting dosage sensitivity.
Hong et al. (2016) found that transgenic mice with the I43N mutation or overexpression of wildtype Pmp2 developed a peripheral neuropathy with impaired motor performance and reduced motor nerve conduction velocities compared to controls. Nerve biopsy from mutant mice showed a reduced number of large myelinated fibers, aberrant myelination, and shorter internodal length compared to controls, suggesting defects in Schwann cell function.
In a father and son (family BAB1468) with demyelinating Charcot-Marie-Tooth disease, type 1G (CMT1G; 618279), Gonzaga-Jauregui et al. (2015) identified a heterozygous c.128T-A transversion in exon 2 of the PMP2 gene, resulting in an ile43-to-asn (I43N) substitution. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. There were several other affected family members from whom DNA was not available. The variant was not found in the Exome Sequencing Project database and was filtered against dbSNP and the 1000 Genomes Project databases. Functional studies of the variant and studies of patient cells were not performed. Expression of the mutant PMP2 protein into zebrafish with morpholino knockdown of the pmp2 orthologs failed to rescue the abnormal motor neuron phenotype and exacerbated the phenotype, consistent with a dominant-negative mechanism. The proband also carried heterozygous missense mutations in the VARS (192150) and PRX (605725) genes, the latter of which is involved in autosomal recessive demyelinating CMT (CMT4F; 614895).
In 3 affected members of a Korean family (family FC183) with CMT1G, Hong et al. (2016) identified a heterozygous c.128T-A transversion (c.128T-A, NM_002677.3) in the PMP2 gene resulting in an I43N substitution at a conserved residue in the lipocalin/cytosolic fatty-acid binding domain. The mutation, which was found by whole-exome sequencing, segregated with the disorder in the family. It was not found in the dbSNP (build 144), 1000 Genomes Project, Exome Sequencing Project, or ExAC databases, or in 500 Korean controls. Studies of patient cells were not performed, but transgenic mice with the I43N mutation developed a peripheral neuropathy similar to that found in the patients (see ANIMAL MODEL).
In a father and son (family 1) with demyelinating Charcot-Marie-Tooth disease, type 1G (CMT1G; 618279), Motley et al. (2016) identified a heterozygous c.155T-C transition in the PMP2 gene, resulting in an ile52-to-thr (I52T) substitution at a conserved residue in the beta barrel of PMP2. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, occurred de novo in the father. The variant was not found in the Exome Variant Server, 1000 Genomes Project, or ExAC databases. Functional studies of the variant and studies of patient cells were not performed, but Motley et al. (2016) suggested that the mutation may result in aberrant transport of fatty acids and possibly result in a toxic gain of function.
Punetha et al. (2018) reported another family with CMT1G due to a heterozygous I52T mutation in the PMP2 gene. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Functional studies of the variant and studies of patient cells were not performed.
In 6 members of a 3-generation Austrian family (family 2) with demyelinating Charcot-Marie-Tooth disease, type 1G (CMT1G; 618279), Motley et al. (2016) identified a heterozygous c.151A-C transversion in the PMP2 gene, resulting in a thr51-to-pro (T51P) substitution at a conserved residue in the beta barrel of PMP2. The mutation, which was found by direct sequencing of the PMP2 gene in 136 European probands with a similar disorder, was confirmed by Sanger sequencing and segregated with the disorder in the family. The variant was not found in the Exome Variant Server, 1000 Genomes Project, or ExAC databases, or in 188 Austrian controls. Functional studies of the variant and studies of patient cells were not performed, but Motley et al. (2016) suggested that the mutation may result in aberrant transport of fatty acids and possibly result in a toxic gain of function.
Ben Othmane, K., Loeb, D., Hayworth-Hodgte, R., Hentati, F., Rao, N., Roses, A. D., Ben Hamida, M., Pericak-Vance, M. A., Vance, J. M. Physical and genetic mapping of the CMT4A locus and exclusion of PMP-2 as the defect in CMT4A. Genomics 28: 286-290, 1995. [PubMed: 8530038] [Full Text: https://doi.org/10.1006/geno.1995.1143]
Gonzaga-Jauregui, C., Harel, T., Gambin, T., Kousi, M., Griffin, L. B., Francescatto, L., Ozes, B., Karaca, E., Jhangiani, S. N., Bainbridge, M. N., Lawson, K. S., Pehlivan, D., and 23 others. Exome sequence analysis suggests that genetic burden contributes to phenotypic variability and complex neuropathy. Cell Rep. 12: 1169-1183, 2015. [PubMed: 26257172] [Full Text: https://doi.org/10.1016/j.celrep.2015.07.023]
Hayasaka, K., Himoro, M., Takada, G., Takahashi, E., Minoshima, S., Shimizu, N. Structure and localization of the gene encoding human peripheral myelin protein 2 (PMP2). Genomics 18: 244-248, 1993. [PubMed: 8288226] [Full Text: https://doi.org/10.1006/geno.1993.1462]
Hayasaka, K., Nanao, K., Tahara, M., Sato, W., Takada, G., Miura, M., Uyemura, K. Isolation and sequence determination of cDNA encoding P2 protein of human peripheral myelin. Biochem. Biophys. Res. Commun. 181: 204-207, 1991. [PubMed: 1720307] [Full Text: https://doi.org/10.1016/s0006-291x(05)81402-0]
Hong, Y. B., Joo, J., Hyun, Y. S., Kwak, G., Choi, Y.-R., Yeo, H. K., Jwa, D. H., Kim, E. J., Mo, W. M., Nam, S. H., Kim, S. M., Yoo, J. H., Koo, H., Park, H. T., Chung, K. W., Choi, B.-O. A mutation in PMP2 causes dominant demyelinating Charcot-Marie-Tooth neuropathy. PLoS Genet. 12: e1005829, 2016. Note: Electronic Article. [PubMed: 26828946] [Full Text: https://doi.org/10.1371/journal.pgen.1005829]
Motley, W. W., Palaima, P., Yum, S. W., Gonzalez, M. A., Tao, F., Wanschitz, J. V., Strickland, A. V., Loscher, W. N., De Vriendt, E., Koppi, S., Medne, L., Janecke, A. R., Jordanova, A., Zuchner, S., Scherer, S. S. De novo PMP2 mutations in families with type I Charcot-Marie-Tooth disease. Brain 139: 1649-1656, 2016. [PubMed: 27009151] [Full Text: https://doi.org/10.1093/brain/aww055]
Narayanan, V., Ripepi, B., Jabs, E. W., Hawkins, A., Griffin, C., Tennekoon, G. Partial structure and mapping of the human myelin P2 protein gene. J. Neurochem. 63: 2010-2013, 1994. [PubMed: 7525873] [Full Text: https://doi.org/10.1046/j.1471-4159.1994.63062010.x]
Punetha, J., Mackay-Loder, L., Harel, T., Coban-Akdemir, Z., Jhangiani, S. N., Gibbs, R. A., Lee, I., Terespolsky, D., Lupski, J. R., Posey, J. E. Identification of a pathogenic PMP2 variant in a multi-generational family with CMT type 1: clinical gene panels versus genome-wide approaches to molecular diagnosis. Molec. Genet. Metab. 125: 302-304, 2018. [PubMed: 30249361] [Full Text: https://doi.org/10.1016/j.ymgme.2018.08.005]