COL7A1 – recessive dystrophic epidermolysis bullosa inversa

COL7A1 encodes type VII collagen, the major component of anchoring fibrils at the dermal–epidermal junction. Biallelic loss-of-function variants in COL7A1 are causative for recessive dystrophic epidermolysis bullosa inversa, an autosomal recessive skin fragility disorder characterized by neonatal generalized blistering that improves with age and evolves into lesions confined to intertriginous areas and mucous membranes.

Genetic evidence includes three unrelated probands: two individuals with RDEB inversa identified among 52 HS-RDEB patients in a multi-patient cohort (PMID:8037207), and a 45-year-old female diagnosed in adulthood based on clinical, ultrastructural, and genetic analyses (PMID:36812272). All cases exhibited compound heterozygous or homozygous nonsense or splice-site mutations with parents as asymptomatic carriers.

Variant spectrum is dominated by premature termination alleles; for example, c.706C>T (p.Arg236Ter) truncates >70% of the protein and abolishes anchoring fibril formation (PMID:8037207). Other reported mutations include canonical splice-site disruptions and small frameshifts, consistently predicting loss of functional collagen VII.

Functional studies demonstrate that compound heterozygous splice-site and frameshift mutations result in markedly reduced alpha1(VII) polypeptides in keratinocytes, absence of extractable collagen VII, and severely hypoplastic anchoring fibrils on electron microscopy (PMID:9284109). These data confirm a loss-of-function mechanism underlies RDEB inversa.

No conflicting reports of non-pathogenic COL7A1 variants in RDEB inversa have been identified. The concordance of genetic findings, ultrastructural pathology, and protein assays supports a cohesive genotype–phenotype relationship.

Key take-home: Detection of biallelic COL7A1 loss-of-function variants confirms the diagnosis of recessive dystrophic epidermolysis bullosa inversa, guiding genetic counseling, carrier testing, and prenatal diagnosis.

References

• Acta dermatovenerologica Croatica • 2022 • Dystrophic Epidermolysis Bullosa Inversa - Case Report and Review of the Literature. PMID:36812272
• 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 Journal of Investigative Dermatology • 1997 • A combination of a common splice site mutation and a frameshift mutation in the COL7A1 gene: absence of functional collagen VII in keratinocytes and skin. PMID:9284109

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