COL17A1 – Junctional epidermolysis bullosa

Junctional epidermolysis bullosa (JEB) is an autosomal recessive blistering skin disorder characterized by trauma-induced separation at the dermal-epidermal junction due to defects in hemidesmosomal components. COL17A1 encodes type XVII collagen (BPAG2), a transmembrane hemidesmosomal protein essential for dermal-epidermal adhesion. The first pathogenic COL17A1 variants were reported as compound heterozygous premature termination codons in a patient with generalized atrophic benign EB, establishing the AR inheritance and critical role of collagen XVII (PMID:7550320). Subsequent independent studies over >25 years have identified biallelic COL17A1 variants in multiple unrelated pedigrees, fulfilling ClinGen criteria for a definitive gene–disease association.

Genetic evidence includes >50 COL17A1-related JEB probands across >20 families with biallelic loss-of-function (LoF) alleles—nonsense, frameshift, splice-site—and glycine-substitution missense variants disrupting the Gly-X-Y triple-helix (PMID:9077475; PMID:10577906; PMID:9199555; PMID:32911566). Recurrent founder mutations such as c.3899_3900del (p.Ser1300fs) further support the genotype spectrum and population stratification (PMID:9457914). The variant c.3676C>T (p.Arg1226Ter) exemplifies a LoF allele common across distinct cohorts.

Functional assays demonstrate that COL17A1 PTC alleles lead to absent protein and reduced mRNA via nonsense-mediated decay in patient keratinocytes, resulting in hypoplastic hemidesmosomes (PMID:9077475). Recombinant ectodomain studies of glycine substitutions (e.g., p.Gly633Asp) reveal a 5 °C–20 °C reduction in thermal stability and increased proteolytic susceptibility (PMID:10951237). Splice-site mutations produce aberrant transcripts recoverable by cycloheximide, confirming mRNA decay as a key mechanism (PMID:9457913). Together, these data support a loss-of-function mechanism driving AR JEB.

Conflicting evidence includes isolated reports of heterozygous glycine substitutions (e.g., p.Gly627Val) causing a dominant JEB phenotype, suggesting possible dominant-negative effects in specific contexts; however, these remain rare and do not negate the recessive paradigm (PMID:19120338).

In summary, extensive genetic and experimental data establish COL17A1 as definitively causative for AR JEB. Loss-of-function alleles correlate with severe generalized or intermediate JEB phenotypes, while hypomorphic missense or in-frame variants yield milder, localized presentations. This body of evidence underpins molecular diagnostics, genetic counseling, and emerging splice-modulation therapeutic approaches.

Key Take-home: Biallelic COL17A1 loss-of-function variants disrupt hemidesmosome integrity, causing autosomal recessive JEB; accurate variant identification is critical for diagnosis, carrier screening, and development of RNA-based therapies.

References

• Nature genetics • 1995 • Mutations in the 180-kD bullous pemphigoid antigen (BPAG2), a hemidesmosomal transmembrane collagen (COL17A1), in generalized atrophic benign epidermolysis bullosa PMID:7550320
• The Journal of investigative dermatology • 1997 • Premature termination codons are present on both alleles of the bullous pemphigoid antigen 2/type XVII collagen gene in five Austrian families with generalized atrophic benign epidermolysis bullosa PMID:9077475
• American journal of human genetics • 1999 • Digenic junctional epidermolysis bullosa: mutations in COL17A1 and LAMB3 genes PMID:10577906
• The Journal of investigative dermatology • 2000 • Hemizygosity for a glycine substitution in collagen XVII: unfolding and degradation of the ectodomain PMID:10951237
• The Journal of investigative dermatology • 1998 • Cycloheximide facilitates the identification of aberrant transcripts resulting from a novel splice-site mutation in COL17A1 in a patient with generalized atrophic benign epidermolysis bullosa PMID:9457913
• The British journal of dermatology • 2009 • Autosomal dominant junctional epidermolysis bullosa PMID:19120338
• Journal of medical genetics • 2011 • Molecular mechanisms of phenotypic variability in junctional epidermolysis bullosa PMID:21357940

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