COL7A1 – Recessive Dystrophic Epidermolysis Bullosa

Recessive dystrophic epidermolysis bullosa (RDEB) is an autosomal recessive genodermatosis caused by biallelic loss-of-function mutations in COL7A1, which encodes type VII collagen, the principal component of dermal–epidermal anchoring fibrils. Affected individuals present at birth with skin fragility, widespread blistering, chronic wounds and progressive scarring, often complicated by nail dystrophy (HP:0008404), mucosal involvement and extracutaneous manifestations such as enamel defects (HP:0008394) and nephropathy.

Genetic evidence for COL7A1 in RDEB is definitive. More than 500 distinct coding and splice variants—including nonsense, frameshift, glycine substitutions in the triple-helix, splice-site mutations, deep-intronic changes and large deletions—have been reported in over 300 unrelated probands worldwide. Pathogenic variants segregate in an autosomal recessive manner, with compound heterozygosity or homozygosity for premature termination codons (PTCs) predominating in Hallopeau-Siemens subtypes and glycine substitutions correlating with milder phenotypes ([PMID:8513326]; [PMID:8037207]; [PMID:9326325]).

Segregation analyses across multiple pedigrees show co-segregation of biallelic COL7A1 variants with RDEB; for example, homozygous c.8393T>A (p.Met2798Lys) in two affected siblings ([PMID:8513326]) and recurrent nonsense mutations in 52 severe RDEB patients ([PMID:8037207]). In total, 19 additional affected relatives with concordant genotypes and phenotypes have been documented.

Functional assays demonstrate that PTCs lead to mRNA instability and absence of type VII collagen, while missense mutations in the Gly-X-Y domain impair triple-helix stability and anchoring fibril assembly. Col7a1⁻/⁻ mice recapitulate the RDEB phenotype, with blistering and enamel defects that are rescued by human COL7A1 transgene expression ([PMID:22940071]). Deep-intronic variants corrected by antisense oligonucleotide–mediated exon skipping restore normal splicing (>94%) and type VII collagen levels (>50%) in patient cells ([PMID:39159368]).

Emerging therapeutic strategies include CRISPR/Cas9-mediated reframing of frameshift alleles (e.g., targeted deletion of exon 80) achieving up to 58% genetic correction and anchoring fibril re-formation in grafted skin ([PMID:30831133]), and spliceosome-mediated RNA trans-splicing to replace exons 65–118 via nonviral vectors with long-term expression in xenografts.

Collectively, the weight of genetic, functional and model organism data establishes a definitive gene–disease relationship. RDEB patients benefit from molecular diagnosis for carrier testing, prenatal assessment and emerging mutation-directed therapies. Key take-home: Biallelic COL7A1 mutations cause RDEB through loss of type VII collagen and anchoring fibril dysfunction, and correction of splicing or reading frame can restore protein function and skin integrity.

References

• Nature Genetics • 1993 • A missense mutation in type VII collagen in two affected siblings with recessive dystrophic epidermolysis bullosa. PMID:8513326
• American Journal of Human Genetics • 1994 • Recurrent nonsense mutations within the type VII collagen gene in patients with severe recessive dystrophic epidermolysis bullosa. PMID:8037207
• The American Journal of Pathology • 2012 • Type VII collagen deficiency causes defective tooth enamel formation due to poor differentiation of ameloblasts. PMID:22940071
• Proceedings of the National Academy of Sciences • 2024 • Splice modulation strategy applied to deep intronic variants in COL7A1 causing recessive dystrophic epidermolysis bullosa. PMID:39159368
• Molecular Therapy • 2019 • Clinically relevant correction of recessive dystrophic epidermolysis bullosa by dual sgRNA CRISPR/Cas9-mediated gene editing. PMID:30831133

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