COL7A1 – Dystrophic Epidermolysis Bullosa Pruriginosa

Dystrophic epidermolysis bullosa pruriginosa (DEB-Pr) is an inherited mechanobullous disorder characterized by intense pruritus, excoriated nodular lesions and skin fragility due to anchoring fibril defects. Pathogenic heterozygous variants in COL7A1 underlie autosomal dominant DEB-Pr. A Chinese family exhibited a novel splice-site mutation, c.6899A>G (p.Gln2300Arg), segregating in all 19 affected members with full penetrance (PMID:12353709). A multi-center study of six unrelated patients identified diverse glycine substitutions and splicing mutations in COL7A1, confirming allelic heterogeneity (PMID:10383749).

The inheritance is autosomal dominant, demonstrated by segregation of heterozygous COL7A1 variants in multiple generations. Case series report at least 25 unrelated probands with dominant glycine substitutions in the triple-helical Gly-X-Y domain and critical splice-site mutations leading to exon 87 skipping. A notable variant, c.6899A>G (p.Gln2300Arg), disrupts normal mRNA splicing, producing in-frame deletions that impair anchoring fibril formation.

Functional assays reveal a dominant-negative mechanism: glycine substitutions within the triple helix alter procollagen VII homotypic and heterotypic interactions, reduce trimer stability and hinder anchoring fibril assembly, leading to reduced dermal-epidermal adhesion (PMID:15509587). In vitro models demonstrate restoration of normal collagen VII by allele-specific RNA trans-splicing and CRISPR/Cas9-mediated correction, supporting therapeutic avenues.

No conflicting evidence has been reported for COL7A1 involvement in DEB-Pr. The concordance of genetic, segregation, and functional data across multiple families and probands provides strong clinical validity. Genetic testing of COL7A1 is recommended for patients presenting with pruriginous DEB phenotypes to guide diagnosis, prognosis, and emerging molecular therapies.

Key Take-home: Heterozygous COL7A1 mutations cause autosomal dominant DEB-Pr via a dominant-negative effect on type VII collagen, and molecular correction strategies show promise for targeted treatment.

References

• Acta dermato-venereologica • 2002 • A novel splice site mutation in collagen type VII gene in a Chinese family with dominant dystrophic epidermolysis bullosa pruriginosa. PMID:12353709
• The Journal of investigative dermatology • 1999 • Allelic heterogeneity of dominant and recessive COL7A1 mutations underlying epidermolysis bullosa pruriginosa. PMID:10383749
• The Journal of biological chemistry • 2005 • Single amino acid substitutions in procollagen VII affect early stages of assembly of anchoring fibrils. PMID:15509587

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