Incidental Mutation 'P0008:Pkp1'

• ID: 7568
• Institutional Source: Beutler Lab
• Gene Symbol: Pkp1
• Ensembl Gene: ENSMUSG00000026413
• Gene Name: plakophilin 1
• MMRRC Submission: 038264-MU
• Essential gene?: Possibly essential (E-score: 0.618)
• Stock #: P0008 (G1)
• Status: Validated
• Chromosome: 1
• Chromosomal Location: 135799133-135846945 bp(-) (GRCm39)
• Type of Mutation: missense
• DNA Base Change (assembly): T to C at 135803421 bp (GRCm39)
• Zygosity: Heterozygous
• Amino Acid Change: Methionine to Valine at position 712 (M712V)
• Ref Sequence: ENSEMBL: ENSMUSP00000128418
• Gene Model: predicted gene model for transcript(s): [ENSMUST00000027667] [ENSMUST00000163260] [ENSMUST00000189805]
• AlphaFold: P97350
• Predicted Effect: probably benign; Transcript: ENSMUST00000027667; AA Change: M712V; PolyPhen 2 Score 0.001 (Sensitivity: 0.99; Specificity: 0.15)
• SMART Domains: Protein: ENSMUSP00000027667; Gene: ENSMUSG00000026413; AA Change: M712V

Domain	Start	End	E-Value	Type
low complexity region	52	60	N/A	INTRINSIC
ARM	277	317	2.65e-9	SMART
ARM	319	360	3.47e-4	SMART
ARM	361	416	1.3e1	SMART
ARM	417	464	5.59e1	SMART
ARM	516	557	8.48e1	SMART
ARM	565	604	3.85e0	SMART
ARM	605	650	5.76e1	SMART

• Predicted Effect: noncoding transcript; Transcript: ENSMUST00000132793
• Predicted Effect: probably benign; Transcript: ENSMUST00000163260; AA Change: M712V; PolyPhen 2 Score 0.001 (Sensitivity: 0.99; Specificity: 0.15)
• SMART Domains: Protein: ENSMUSP00000128418; Gene: ENSMUSG00000026413; AA Change: M712V

Domain	Start	End	E-Value	Type
low complexity region	52	60	N/A	INTRINSIC
ARM	277	317	2.65e-9	SMART
ARM	319	360	3.47e-4	SMART
ARM	361	416	1.3e1	SMART
ARM	417	464	5.59e1	SMART
ARM	516	557	8.48e1	SMART
ARM	565	604	3.85e0	SMART
ARM	605	650	5.76e1	SMART

• Predicted Effect: probably benign; Transcript: ENSMUST00000189805
• SMART Domains: Protein: ENSMUSP00000140883; Gene: ENSMUSG00000026413

Domain	Start	End	E-Value	Type
low complexity region	52	60	N/A	INTRINSIC

• Meta Mutation Damage Score: 0.0898
• Coding Region Coverage:
  • 1x: 86.8%
  • 3x: 83.1%
  • 10x: 72.7%
  • 20x: 59.5%
• Validation Efficiency: 70% (420/599)
• MGI Phenotype: FUNCTION: [Summary is not available for the mouse gene. This summary is for the human ortholog.] This gene encodes a member of the arm-repeat (armadillo) and plakophilin gene families. Plakophilin proteins contain numerous armadillo repeats, localize to cell desmosomes and nuclei, and participate in linking cadherins to intermediate filaments in the cytoskeleton. This protein may be involved in molecular recruitment and stabilization during desmosome formation. Mutations in this gene have been associated with the ectodermal dysplasia/skin fragility syndrome. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2010] ; PHENOTYPE: Mice homozygous for a knock-out allele exhibit reduced birth weight, absent whiskers, and neonatal lethality associated with skin fragility, skin lesions, loss of desmosomal adhesion, and impaired skin barrier function due to abnormal tight junction formation. [provided by MGI curators]
• Allele List at MGI:

  All alleles(4) : Targeted(4)

• Posted On: 2012-10-04
• Science Writer: Anne Murray

Protein Function and Prediction

Plakophilin 1 (Pkp1) is a member of the armadillo family, a family that functions in cytoskeleton/cell membrane interactions, linkers between adherens junctions and desmsomes at the plasma membrane, and signal transduction (OMIM: *601975; (1)).

Expression/Localization

Pkp1 is expressed at desmosomal cell junctions at the site of intermediate filament interaction (OMIM: *601975).  The two isoforms of Pkp1 are uniquely localized: Pkp1a is localized to the nucleus and at the desmosomal plaques, while Pkp1b is exclusively expressed in the nucleus (2).

Background

Mutations in PKP1 can cause ectodermal dysplasia/skin fragility syndrome (OMIM: #604536), a condition in which patients have trauma-induced skin fragility and congenital ectodermal dysplasia affecting hair, nails, and sweat glands (3-6).  Patients with this condition can develop severe blistering of the skin and desquamation that will progress to skin fragility and trauma-induced tearing (4).  Examination of the skin identified thickening of the epidermis and widening of keratinocyte intercellular spaces (4).  Also, electron microscopy of the skin showed loss keratinocyte-keratinocyte.  Also desmosomes were small and reduced in number (4).  Another study found that lack of PKP1 in vitro results in increased keratinocyte migration and reduced desmosome stability (7).

References

  1. South, A. P. (2004) Plakophilin 1: An Important Stabilizer of Desmosomes. Clin Exp Dermatol. 29, 161-167.

  2. Schmidt, A., Langbein, L., Pratzel, S., Rode, M., Rackwitz, H. R., and Franke, W. W. (1999) Plakophilin 3--a Novel Cell-Type-Specific Desmosomal Plaque Protein. Differentiation. 64, 291-306.

  3. McGrath, J. A., Hoeger, P. H., Christiano, A. M., McMillan, J. R., Mellerio, J. E., Ashton, G. H., Dopping-Hepenstal, P. J., Lake, B. D., Leigh, I. M., Harper, J. I., and Eady, R. A. (1999) Skin Fragility and Hypohidrotic Ectodermal Dysplasia Resulting from Ablation of Plakophilin 1. Br J Dermatol. 140, 297-307.

  4. McGrath, J. A., McMillan, J. R., Shemanko, C. S., Runswick, S. K., Leigh, I. M., Lane, E. B., Garrod, D. R., and Eady, R. A. (1997) Mutations in the Plakophilin 1 Gene Result in Ectodermal dysplasia/skin Fragility Syndrome. Nat Genet. 17, 240-244.

  5. Boyce, A. E., McGrath, J. A., Techanukul, T., Murrell, D. F., Chow, C. W., McGregor, L., and Warren, L. J. (2012) Ectodermal Dysplasia-Skin Fragility Syndrome due to a New Homozygous Internal Deletion Mutation in the PKP1 Gene. Australas J Dermatol. 53, 61-65.

  6. Zheng, R., Bu, D. F., and Zhu, X. J. (2005) Compound Heterozygosity for New Splice Site Mutations in the Plakophilin 1 Gene (PKP1) in a Chinese Case of Ectodermal Dysplasia-Skin Fragility Syndrome. Acta Derm Venereol. 85, 394-399.

  7. South, A. P., Wan, H., Stone, M. G., Dopping-Hepenstal, P. J., Purkis, P. E., Marshall, J. F., Leigh, I. M., Eady, R. A., Hart, I. R., and McGrath, J. A. (2003) Lack of Plakophilin 1 Increases Keratinocyte Migration and Reduces Desmosome Stability. J Cell Sci. 116, 3303-3314.