HGNC Approved Gene Symbol: PRPH
Cytogenetic location: 12q13.12 Genomic coordinates (GRCh38): 12:49,295,147-49,298,686 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 12q13.12 | {Amyotrophic lateral sclerosis, susceptibility to} | 105400 | Autosomal dominant; Autosomal recessive | 3 |
Peripherin, a type III intermediate filament protein, was initially described by Portier et al. (1984) as a cytoskeletal protein present in neurons of the mammalian peripheral nervous system (hence, the name) and in cultured neuroblastoma cells.
Leonard et al. (1988) reported that a clone isolated from a rat pheochromocytoma cell line encoded an intermediate filament protein that showed high homology to desmin (125660) and vimentin (193060), and contains a conserved central alpha-helical rod domain with the characteristic heptad repeat of hydrophobic residues. The amino-terminal region contained potential serine phosphorylation sites. Northern blot analysis detected a corresponding mRNA in ganglia of the peripheral nervous system, including the superior cervical ganglion, ciliary ganglion, and dorsal root ganglion. In the central nervous system, expression was detected in motor nuclei of cranial nerves and ventral horn neurons. Expression was induced by nerve growth factor (see NGFB; 162030).
Thompson and Ziff (1989) cloned the rat peripherin gene and determined that the peripherin protein is a type III intermediate filament protein.
Foley et al. (1994) isolated a cDNA corresponding to the human peripherin gene from a human placenta cosmid library. The predicted 475-amino acid sequence showed 96%, 95%, and 71% identity to the rat, mouse, and Xenopus sequences, respectively.
Foley et al. (1994) determined that the PRPH gene contains 9 exons.
By in situ hybridization, Moncla et al. (1992) assigned the mouse and human peripherin genes to chromosomes 15 and 12q12-q13, respectively. The authors noted that these regions show syntenic homology, containing other intermediate filament genes (e.g., keratins) and other genes which may be coordinately regulated.
Pendleton et al. (1991) assigned the peripherin gene to mouse chromosome 15 by study of a panel of mouse/Chinese hamster somatic cell hybrids.
Oblinger et al. (1989) found that peripherin expression was increased in rat dorsal root ganglion cells and in large- and medium-sized neurons after peripheral axotomy. The findings suggested a role for the protein in axonal regrowth.
In the nonobese diabetic (NOD) mouse, a model of autoimmune diabetes, Boitard et al. (1992) identified autoantibodies directed against a 58-kD islet antigen identified as peripherin.
He and Hays (2004) identified Lewy body-like ubiquitinated (see UBB; 191339) inclusions in motor neurons from 9 of 40 patients with amyotrophic lateral sclerosis (ALS; 105400); all of the inclusions expressed peripherin. Similar inclusions were not identified in 39 controls.
In 1 of 189 ALS patients (105400), Gros-Louis et al. (2004) identified a 1-bp deletion in the PRPH gene (170710.0001), suggesting that the mutation conferred an increased susceptibility to development of the disease.
This peripherin gene, PRPH, is distinct from the photoreceptor type of peripherin (PRPH2; 179605), which is mutant in a form of retinitis pigmentosa (608133) in the human and the mouse. The PRPH2 gene maps to human chromosome 6 and mouse chromosome 17.
Beaulieu et al. (1999) found that overexpression of wildtype peripherin in mice resulted in massive and selective degeneration of motor axons beginning after 2 years of age. Microscopic examination of the mice showed a loss of approximately 35% of ventral root motor axons as well as increased peripherin staining and inclusions in motor neurons and neurites. Overexpression of peripherin in neurofilament light protein (NFL; 162280)-null mice resulted in more severe disease with earlier onset (14 months of age) and a loss of 45 to 59% motor axons and 64% spinal motor neurons. Beaulieu et al. (1999) noted that increased expression of the wildtype protein suggests an alternate mechanism for the development of inclusion bodies, and they proposed that upregulation of peripherin could be a regenerative response in ALS.
Robertson et al. (2003) noted that there are 3 isoforms of mouse peripherin: Per58, Per56, and Per61. Per61 contains a 32-amino acid insertion in coil 2 of the alpha-helical rod domain, representing the inclusion of intron 4. In vitro, Per61 was unable to assemble properly, forming intracellular aggregates, and was neurotoxic to motor neurons, causing cell death within 7 days. In vivo, Per61 expression was detected in motor neurons of transgenic ALS mice expressing the SOD1 G37R (147450.0001) mutation, and in pathologic spinal cord lesions in 2 of 3 familial ALS patients. Robertson et al. (2003) concluded that alternatively spliced variants of peripherin may contribute to neurodegeneration in ALS.
In 1 of 189 ALS patients (105400), Gros-Louis et al. (2004) identified a heterozygous 1-bp deletion in exon 1 of the PRPH gene (228delC), resulting in a truncated protein of 85 amino acids. The mutation was not detected in 190 normal controls. The patient was a woman with sporadic disease characterized by onset at age 60 years and death at age 65 years. In vitro expression studies showed that the 228delC mutation resulted in decreased peripherin immunoreactivity. Cotransfection of the mutated peripherin with the neurofilament-light protein (NFL; 162280) resulted in increased PRPH expression but disruption of the intermediate filament network. The authors noted that Charcot-Marie-Tooth disease type 2E (607684) is caused by mutation in the NFL gene, indicating that defects in neurofilaments can lead to neurologic disease. Gros-Louis et al. (2004) concluded that PRPH mutations may be responsible for a small percentage of ALS cases and that neurofilament disorganization may contribute to disease pathogenesis.
In 1 of 30 unrelated patients with ALS (105400), Leung et al. (2004) identified a homozygous G-to-T transversion in exon 1 of the PRPH gene, resulting in an asp141-to-tyr (D141Y) substitution in a highly conserved residue within the linker region between coil 1a and 1b of the rod domain. The D141Y substitution was not identified in 200 control chromosomes. The patient was a 42-year-old man who first developed difficulty manipulating small objects with his left hand. Weakness progressed to involve all 4 limbs, and he developed dysarthria and dysphagia. He later developed hand muscle wasting and upper motor neuron signs and died of respiratory failure 3 years after onset. Postmortem examination confirmed the diagnosis of ALS. A few motor neurons in the spinal cord contained large filamentous inclusions that were immunoreactive for peripherin and other neurofilament triplet proteins, although they were not ubiquitinated. In vitro expression studies showed that cells transfected with the D141Y mutant protein developed filamentous aggregates.
Beaulieu, J.-M., Nguyen, M. D., Julien, J.-P. Late onset death of motor neurons in mice overexpressing wild-type peripherin. J. Cell Biol. 147: 531-544, 1999. [PubMed: 15132161] [Full Text: https://doi.org/10.1083/jcb.147.3.531]
Boitard, C., Villa, M. C., Becourt, C., Pham Gia, H., Huc, C., Sempe, P., Portier, M. M., Bach, J. F. Peripherin: an islet antigen that is cross-reactive with nonobese diabetic mouse class II gene products. Proc. Nat. Acad. Sci. 89: 172-176, 1992. [PubMed: 1729686] [Full Text: https://doi.org/10.1073/pnas.89.1.172]
Foley, J., Ley, C. A., Parysek, L. M. The structure of the human peripherin gene (PRPH) and identification of potential regulatory elements. Genomics 22: 456-461, 1994. [PubMed: 7806235] [Full Text: https://doi.org/10.1006/geno.1994.1410]
Gros-Louis, F., Lariviere, R., Gowing, G., Laurent, S., Camu, W., Bouchard, J.-P., Meininger, V., Rouleau, G. A., Julien, J.-P. A frameshift deletion in peripherin gene associated with amyotrophic lateral sclerosis. J. Biol. Chem. 279: 45951-45956, 2004. [PubMed: 15322088] [Full Text: https://doi.org/10.1074/jbc.M408139200]
He, C. Z., Hays, A. P. Expression of peripherin in ubiquinated (sic) inclusions of amyotrophic lateral sclerosis. J. Neurol. Sci. 217: 47-54, 2004. [PubMed: 14675609] [Full Text: https://doi.org/10.1016/j.jns.2003.08.016]
Leonard, D. G., Gorham, J. D., Cole, P., Greene, L. A., Ziff, E. B. A nerve growth factor-regulated messenger RNA encodes a new intermediate filament protein. J. Cell Biol. 106: 181-193, 1988. [PubMed: 3339087] [Full Text: https://doi.org/10.1083/jcb.106.1.181]
Leung, C. L., He, C. Z., Kaufmann, P., Chin, S. S., Naini, A., Liem, R. K. H., Mitsumoto, H., Hays, A. P. A pathogenic peripherin gene mutation in a patient with amyotrophic lateral sclerosis. Brain Path. 14: 290-296, 2004. [PubMed: 15446584] [Full Text: https://doi.org/10.1111/j.1750-3639.2004.tb00066.x]
Moncla, A., Landon, F., Mattei, M.-G., Portier, M.-M. Chromosomal localisation of the mouse and human peripherin genes. Genet. Res. 59: 125-129, 1992. [PubMed: 1378416] [Full Text: https://doi.org/10.1017/s0016672300030330]
Oblinger, M. M., Wong, J., Parysek, L. M. Axotomy-induced changes in the expression of a type III neuronal intermediate filament gene. J. Neurosci. 9: 3766-3775, 1989. [PubMed: 2585054] [Full Text: https://doi.org/10.1523/JNEUROSCI.09-11-03766.1989]
Pendleton, J. W., Violette, S. M., Hunihan, L. W., Greene, L. A., Ruddle, F. H. The peripherin gene maps to mouse chromosome 15. Genomics 9: 369-372, 1991. [PubMed: 2004788] [Full Text: https://doi.org/10.1016/0888-7543(91)90267-i]
Portier, M.-M., de Nechaud, B., Gros, F. Peripherin, a new member of the intermediate filament protein family. Dev. Neurosci. 6: 335-344, 1984.
Robertson, J., Doroudchi, M. M., Nguyen, M. D., Durham, H. D., Strong, M. J., Shaw, G., Julien, J.-P., Mushynski, W. E. A neurotoxic peripherin splice variant in a mouse model of ALS. J. Cell Biol. 160: 939-949, 2003. [PubMed: 12642616] [Full Text: https://doi.org/10.1083/jcb.200205027]
Thompson, M. A., Ziff, E. B. Structure of the gene encoding peripherin, an NGF-regulated neuronal-specific type III intermediate filament protein. Neuron 2: 1043-1053, 1989. [PubMed: 2624740] [Full Text: https://doi.org/10.1016/0896-6273(89)90228-6]