HGNC Approved Gene Symbol: PKP1
SNOMEDCT: 716699004;
Cytogenetic location: 1q32.1 Genomic coordinates (GRCh38): 1:201,283,506-201,332,989 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1q32.1 | Ectodermal dysplasia/skin fragility syndrome | 604536 | Autosomal recessive | 3 |
Plakoglobin (JUP; 173325) was first identified as a protein of the desmosomal type of cell junction. It is a component of the plaque, i.e., that part of the desmosome in the cytoplasm with which the intermediate filaments interact. Another desmosomal component, plakophilin, originally known as band 6 protein, was cloned and sequenced in human and bovine by Hatzfeld et al. (1994) and Heid et al. (1994).
Schmidt et al. (1997) determined that there are at least 2 isoforms of the PKP1 protein: PKP1a with 726 amino acids and PKP1b with 747 amino acids. PKP1b is located exclusively in nuclei, whereas PKP1a is located in nuclei as well as in desmosomal plaques of stratified and complex epithelia.
Schmidt et al. (1997) found that the primary PKP1 transcript spans approximately 50 kb and contains 15 exons, and identified exon 7 as the alternatively used exon, leading to splice variant PKP1b. Each mRNA splice form can occur in 2 polyadenylation forms of approximately 2.7 and 5.3 kb.
Using immunohistochemistry and quantitative electron microscopy, McMillan et al. (2003) examined suprabasal desmosomes from 3 PKP1-deficient patients, an unaffected carrier with a PKP1-heterozygous acceptor splice site mutation, and 5 healthy control subjects. Compared with those in controls, desmosomes in PKP1-null patients were reduced dramatically both in size (49%) and frequency (61%) in the lower suprabasal layers (P less than 0.01). In the lower suprabasal compartment of the heterozygous carrier, corresponding reductions were 37% and 20%, respectively (P less than 0.01). Surprisingly, in the PKP1-null patients' upper suprabasal layer, desmosome size was larger (59%, P less than 0.01) than the control value, and showed increased desmoglein-1 (125670) and PKP2 (602861) staining. The upper suprabasal layer desmosome frequency in PKP1-null patients was similar to that seen in the lower suprabasal compartment but reduced by 43% compared to controls. The carrier showed no difference in the upper suprabasal layer desmosome size and frequency compared with the controls (P greater than 0.05). The PKP1-null patients showed poorly developed inner and outer desmosomal plaques. Thus, both the patients and unaffected carrier showed reductions in the lower suprabasal layer desmosome size and number, despite only PKP1-null patients exhibiting any phenotype. These findings attest to the molecular recruiting and stabilizing roles of PKP1 in desmosome formation, particularly in the lower suprabasal compartment.
Cowley et al. (1997) used PCR analysis of monochromosomal somatic cell hybrids to map the PKP1 gene to chromosome 1; fluorescence in situ hybridization showed that the gene resides on the distal portion of 1q. By fluorescence in situ hybridization and analysis of a somatic cell hybrid mapping panel, Bonne et al. (1998) refined the mapping of the PKP1 gene to 1q32.
Members of the armadillo protein gene family, which includes plakoglobin and beta-catenin (116806), have important functions in cytoskeleton/cell membrane interactions. These proteins may act as linker molecules at adherens junctions and desmosomes at the plasma membrane; in addition, they may have pivotal roles in signal transduction pathways and significant effects on cell behavior during development. McGrath et al. (1997) described the first human mutations in 1 of these dual function proteins. A 6-year-old boy with the ectodermal dysplasia/skin fragility syndrome (EDSFS; 604536) showed complete absence of immunostaining for plakophilin-1 in the skin and was found to be a compound heterozygote for 2 nonsense mutations of the PKP1 gene (601975.0001 and 601975.0002). Clinically, there were features of both cutaneous fragility and congenital ectodermal dysplasia affecting skin, hair, and nails. There was no evidence of significant abnormalities in other epithelia or tissues. Desmosomes in the skin were small and poorly formed with widening of keratinocyte intercellular spaces and perturbed desmosome/keratin intermediate filament interactions. The molecular findings and clinical observations in this patient attested to the dual importance of plakophilin-1 in both cutaneous cell-cell adhesion and epidermal morphogenesis.
In a 17-year-old patient with ectodermal dysplasia/skin fragility syndrome, Whittock et al. (2000) identified a homozygous splice site mutation in the PKP1 gene (601975.0003).
In a 42-year-old man with a milder than usual form of EDSFS, Hamada et al. (2002) identified a homozygous splice site mutation in the PKP1 gene (601975.0004). RT-PCR using RNA extracted from a skin biopsy revealed evidence for residual low levels of full-length wildtype transcript (approximately 8%) as well as multiple other nearly full-length transcripts. The authors suggested that this may account for the milder phenotype in this patient.
In a 6-year-old boy with EDSFS, Ersoy-Evans et al. (2006) identified a homozygous deletion in the PKP1 gene (601975.0005).
In a 15-year-old boy with EDSFS, Hernandez-Martin et al. (2013) identified a homozygous splice site mutation in the PKP1 gene (601975.0006).
McGrath et al. (1997) found compound heterozygosity for 2 nonsense mutations in the PKP1 gene in a 6-year-old boy with the ectodermal dysplasia/skin fragility syndrome (EDSFS; 604536). One allele of the PKF1 gene carried a C-to-T transition that changed a glutamine residue (CAG) to a stop codon (TAG). This mutation was present in the father also. The other allele of the proband carried a 28-bp internal duplication mutation (601975.0002), causing a frameshift and a stop codon 66 bp downstream from the site of the insertion. This mutation was present in the mother. The paternal mutation, gln304 to ter (Q304X), was present within the first repeat domain, while the maternal duplication and downstream premature termination codon resided within the third domain. There was no family history of skin blistering or other significant abnormalities and the parents were unrelated. At birth, the proband's skin was lobster pink generally, with blistering on the soles. Over the first 48 hours, he developed more severe blistering and desquamation on the face, limbs, and buttocks. His hair was short and sparse, and the nails were thickened and dystrophic. Subsequently, his skin continued to show fragility, with trauma-induced tearing and blisters on the pressure points of the soles after prolonged standing or walking.
For discussion of the 28-bp duplication in the PKP1 gene that was found in compound heterozygous state in a patient with the ectodermal dysplasia/skin fragility syndrome (EDSFS; 604536) by McGrath et al. (1997), see 601975.0001. The authors referred to this mutation as 1132ins28.
Whittock et al. (2000) reported a homozygous splice site mutation (1233-2A-T) in the PKP1 gene in a 17-year-old male with the ectodermal dysplasia/skin fragility syndrome (EDSFS; 604536). The clinical features comprised skin erosions, dystrophic nails, sparse hair, and painful thickening and cracking of palms and soles.
In a 42-year-old man with a milder than usual form of ectodermal dysplasia/skin fragility syndrome (EDSFS; 604536), Hamada et al. (2002) identified a homozygous donor splice site mutation (c.2021+1G-A) in intron 11 of the PKP1 gene. RT-PCR using RNA extracted from a skin biopsy from the patient revealed evidence for residual low levels of wildtype transcript (approximately 8%) as well as multiple other, nearly full-length transcripts. This was suggested to account for the milder phenotype in this patient.
In a 6-year-old boy with ectodermal dysplasia/skin fragility syndrome (EDSFS; 604536), Ersoy-Evans et al. (2006) identified a homozygous deletion 1-bp deletion (c.888delC) in exon 5 of the PKP1 gene, resulting in a premature termination codon 123 bp downstream.
In a 15-year-old boy with ectodermal dysplasia/skin fragility syndrome (EDSFS; 604536), Hernandez-Martin et al. (2013) identified a homozygous splice site mutation in intron 6 (c.1233-2A-G) of the PKP1 gene, leading to a frameshift and a premature termination codon (Arg411SerfsTer51).
Bonne, S., van Hengel, J., van Roy, F. Chromosomal mapping of human armadillo genes belonging to the p120(ctn)/plakophilin subfamily. Genomics 51: 452-454, 1998. [PubMed: 9721216] [Full Text: https://doi.org/10.1006/geno.1998.5398]
Cowley, C. M. E., Simrak, D., Spurr, N. K., Arnemann, J., Buxton, R. S. The plakophilin 1 (PKP1) and plakoglobin (JUP) genes map to human chromosomes 1q and 17, respectively. Hum. Genet. 100: 486-488, 1997. [PubMed: 9272178] [Full Text: https://doi.org/10.1007/s004390050539]
Ersoy-Evans, S., Erkin, G., Fassihi, H., Chan, I., Paller, A. S., Surucu, S., McGrath, J. A. Ectodermal dysplasia-skin fragility syndrome resulting from a new homozygous mutation, 888delC, in the desmosomal protein plakophilin 1. J. Am. Acad. Derm. 55: 157-161, 2006. [PubMed: 16781314] [Full Text: https://doi.org/10.1016/j.jaad.2005.10.002]
Hamada, T., South, A. P., Mitsuhashi, Y., Kinebuchi, T., Bleck, O., Ashton, G. H. S., Hozumi, Y., Suzuki, T., Hashimoto, T., Eady, R. A. J., McGrath, J. A. Genotype-phenotype correlation in skin fragility-ectodermal dysplasia syndrome resulting from mutations in plakophilin I. Exp. Derm. 11: 107-114, 2002. [PubMed: 11994137] [Full Text: https://doi.org/10.1034/j.1600-0625.2002.110202.x]
Hatzfeld, M., Kristjansson, G. I., Plessmann, U., Weber, K. Band 6 protein, a major constituent of desmosomes from stratified epithelia, is a novel member of the armadillo multigene family. J. Cell Sci. 107: 2259-2270, 1994. [PubMed: 7527055] [Full Text: https://doi.org/10.1242/jcs.107.8.2259]
Heid, H. W., Schmidt, A., Zimbelmann, R., Schafer, S., Winter-Simanowski, S., Stumpp, S., Keith, M., Figge, U., Schnolzer, M., Franke, W. W. Cell type-specific desmosomal plaque proteins of the plakoglobin family: plakophilin 1 (band 6 protein). Differentiation 58: 113-131, 1994. [PubMed: 7890138] [Full Text: https://doi.org/10.1046/j.1432-0436.1995.5820113.x]
Hernandez-Martin, A., Torrelo, A., Ciria, S., Colmenero, I., Aguilar, A., Grimalt, R., Gonzalez-Sarmiento, R. Ectodermal dysplasia-skin fragility syndrome: a novel mutation in the PKP1 gene. Clin. Exp. Derm. 38: 787-790, 2013. [PubMed: 24073657] [Full Text: https://doi.org/10.1111/ced.12109]
McGrath, J. A., McMillan, J. R., Shemanko, C. S., Runswick, S. K., Leigh, I. M., Lane, E. B., Garrod, D. R., Eady, R. A. J. Mutations in the plakophilin 1 gene result in ectodermal dysplasia/skin fragility syndrome. Nature Genet. 17: 240-244, 1997. [PubMed: 9326952] [Full Text: https://doi.org/10.1038/ng1097-240]
McMillan, J. R., Haftek, M., Akiyama, M., South, A. P., Perrot, H., McGrath, J. A., Eady, R. A. J., Shimizu, H. Alterations in desmosome size and number coincide with the loss of keratinocyte cohesion in skin with homozygous and heterozygous defects in the desmosomal protein plakophilin 1. J. Invest Derm. 121: 96-103, 2003. [PubMed: 12839569] [Full Text: https://doi.org/10.1046/j.1523-1747.2003.12324.x]
Schmidt, A., Langbein, L., Rode, M., Pratzel, S., Zimbelmann, R., Franke, W. W. Plakophilins 1a and 1b: widespread nuclear proteins recruited in specific epithelial cells as desmosomal plaque components. Cell Tissue Res. 290: 481-499, 1997. [PubMed: 9369526] [Full Text: https://doi.org/10.1007/s004410050956]
Whittock, N. V., Haftek, M., Angoulvant, N., Wolf, F., Perrot, H., Eady, R. A. J., McGrath, J. A. Genomic amplification of the human plakophilin 1 gene and detection of a new mutation in ectodermal dysplasia/skin fragility syndrome. J. Invest. Derm. 115: 368-374, 2000. [PubMed: 10951270] [Full Text: https://doi.org/10.1046/j.1523-1747.2000.00082.x]