COL17A1 – Generalized Junctional Epidermolysis Bullosa Non-Herlitz Type

COL17A1 encodes the 180-kDa bullous pemphigoid antigen (BPAG2), also known as type XVII collagen, a transmembrane hemidesmosomal protein critical for dermal–epidermal adhesion in basal keratinocytes. Loss-of-function variants in COL17A1 underlie generalized atrophic benign epidermolysis bullosa (GABEB), a non-lethal autosomal recessive form of junctional epidermolysis bullosa characterized by skin fragility and blistering (PMID:7550320).

Clinical genetic studies demonstrate an autosomal recessive inheritance pattern with biallelic null or splice-site mutations. The index patient was compound heterozygous for c.3827dup (p.Gly1277fs) and c.3676C>T (p.Arg1226Ter), both introducing premature termination codons in COL17A1 (PMID:7550320). Subsequent reports identified homozygous splice-site mutations (c.2336-2A>G) and frameshift insertions (209-210insCA), confirming pathogenicity across diverse populations (PMID:9204958, PMID:16172808).

Segregation analyses in consanguineous and extended families, including a five-generation Palestinian pedigree with a founder donor splice-site mutation c.3418+2del, show concordant recessive inheritance and full penetrance in homozygotes (PMID:14614394). Though specific counts of affected relatives are not always reported, autozygosity mapping and linkage (LOD = 3.08) substantiate familial segregation (PMID:16172808).

The variant spectrum includes frameshift, nonsense, in-frame deletions, splice-site, and founder mutations, with recurrent alleles such as 4003delTC observed in multiple Austrian families over ≥6 generations (PMID:9077475). Missense variants causing glycine substitutions within collagenous domains have also been reported but typically act recessively. Polymorphic alleles (e.g., c.798C>G) are distinguished by lack of disease segregation in carriers (PMID:11912005).

Functional assays corroborate genetic findings: immunofluorescence and immunoblot analyses reveal absent BPAG2/BP180 antigen in patient keratinocytes, while Northern blot and RT-PCR demonstrate reduced or unstable transcripts due to nonsense‐mediated decay (PMID:7883981). Cycloheximide treatment stabilizes PTC‐containing COL17A1 mRNAs, enabling detection of cryptic transcripts and confirming splice-defect mechanisms (PMID:9457913).

No conflicting evidence disputing the COL17A1–GABEB association has been reported. Experimental rescue of aberrant transcripts via spliceosome-mediated RNA trans-splicing (SMaRT) further supports COL17A1 haploinsufficiency as pathogenic (PMID:12631245).

Integration of genetic and functional data yields a Strong clinical validity classification: biallelic COL17A1 LoF variants in multiple unrelated families with concordant recessive segregation and robust mechanistic evidence. Diagnostic sequencing of COL17A1 is recommended for suspected GABEB, and emerging molecular therapies targeting mRNA splicing hold translational promise. Key Take-home: Autosomal recessive COL17A1 LoF variants reliably predict GABEB, guiding clinical diagnosis and therapeutic development.

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 Clinical Investigation • 1995 • 180-kD bullous pemphigoid antigen (BP180) is deficient in generalized atrophic benign epidermolysis bullosa. PMID:7883981
• 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
• 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
• Genetics in Medicine • 2003 • A founder COL17A1 splice site mutation leading to generalized atrophic benign epidermolysis bullosa in an extended inbred Palestinian family from Israel. PMID:14614394
• Journal of Dermatological Science • 2002 • A novel homozygous point mutation in the COL17A1 gene in a Chinese family with generalized atrophic benign epidermolysis bullosa. PMID:11912005

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