PKP1 – Epidermolysis Bullosa Simplex due to Plakophilin Deficiency

The association between PKP1 and epidermolysis bullosa simplex due to plakophilin deficiency is supported by a robust body of clinical evidence. Multiple independent case reports and multi‐patient studies have consistently documented infants and children presenting with skin fragility, nail dystrophy, and palmoplantar hyperkeratosis, among other ectodermal anomalies. In several instances, affected individuals exhibited additional features such as global developmental delay and woolly scalp hair. This broad phenotypic spectrum is in keeping with a pathogenic role for loss‐of‐function variants in PKP1. The literature underscores that PKP1 mutations disrupt desmosomal structure, leading to compromised epidermal adhesive integrity (PMID:21727700).

Genetic evidence points to an autosomal recessive mechanism, with multiple unrelated probands demonstrating biallelic pathogenic variants. Several reports detail compound heterozygous or homozygous loss‐of‐function mutations – including splice site, deletion, and frameshift changes – that result in truncated or absent plakophilin 1 protein. For example, in one study a novel deletion, reported as c.897_902del (p.Gln301_Asn302del), was identified in a patient manifesting the full clinical spectrum of the disorder (PMID:22309335). The recurrent detection of deleterious variants, along with evidence of segregation among affected family members, bolsters the gene-disease causality.

A review of the variant spectrum reveals that both small deletions and splice site alterations predominate. Reported variants are often loss‐of‐function in nature, consistent with the absence or marked reduction of functional plakophilin 1 in skin biopsies from affected individuals. Notably, the selected variant, c.897_902del (p.Gln301_Asn302del), exemplifies the disruption of the protein’s structural integrity. The presence of multiple independent variants across different ethnic groups further confirms the pathogenicity of PKP1 alterations in this syndrome (PMID:25565931).

Functional studies substantiate the clinical and genetic findings by demonstrating that loss of PKP1 expression leads to desmosomal defects. Skin biopsies consistently reveal acantholysis, reduced desmosome numbers, and widening of intercellular spaces, which directly correlate with the clinical features of skin fragility and hyperkeratosis. Experimental models have replicated these findings, showing impaired cell-cell adhesion upon PKP1 knockdown. These data confirm the mechanistic basis of the phenotype, implicating a loss-of-function mechanism for this gene (PMID:19945625).

Integrating genetic and functional data, the evidence convincingly supports a strong gene-disease association. Numerous studies, encompassing over six independent probands and multiple affected families, have revealed pathogenic biallelic alterations in PKP1. Functional assessments further validate that these variants lead to desmosomal instability, which is central to the clinical manifestations of epidermolysis bullosa simplex due to plakophilin deficiency. Although additional evidence exists beyond the ClinGen scoring cap, the current data are directly applicable to diagnostic decision-making and therapeutic strategy formulation.

Key Take‑home: PKP1 loss‐of‐function is a well‑established cause of epidermolysis bullosa simplex due to plakophilin deficiency, offering clear clinical utility for diagnosis and management.

References

• Indian journal of dermatology, venereology and leprology • 2011 • Ectodermal dysplasia-skin fragility syndrome PMID:21727700
• The Australasian journal of dermatology • 2012 • Ectodermal dysplasia-skin fragility syndrome due to a new homozygous internal deletion mutation in the PKP1 gene PMID:22309335
• Clinical and experimental dermatology • 2013 • Ectodermal dysplasia-skin fragility syndrome: a novel mutation in the PKP1 gene PMID:24073657
• Molecular syndromology • 2014 • A plakophilin-1 gene mutation in an Egyptian family with ectodermal dysplasia-skin fragility syndrome PMID:25565931
• The Journal of dermatology • 2020 • Novel homozygous deletion of the plakophilin-1 gene in a Chinese patient with ectodermal dysplasia-skin fragility syndrome PMID:32346906
• Journal of the American Academy of Dermatology • 2006 • Ectodermal dysplasia-skin fragility syndrome resulting from a new homozygous mutation, 888delC, in the desmosomal protein plakophilin 1 PMID:16781314
• Dermatologic clinics • 2010 • Ectodermal dysplasia-skin fragility syndrome PMID:19945625

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