KRT5 – Epidermolysis Bullosa Simplex with Mottled Pigmentation

Epidermolysis bullosa simplex with mottled pigmentation (EBS-MP) is a rare autosomal dominant skin disorder characterized by intraepidermal blistering after minor trauma, reticular hyperpigmentation, nail dystrophy, and mild palmoplantar keratosis. The gene KRT5, encoding keratin 5, is essential for basal keratinocyte cytoskeleton integrity and is implicated in multiple EBS subtypes, including EBS-MP (PMID:10494094).

Initial linkage and mutation analyses in two unrelated families demonstrated a C>T transition at codon 24 of KRT5 (c.71C>T (p.Thr24Ile)) that segregated with disease and was absent in 100 control alleles (PMID:8799157; PMID:9129237). Subsequent reports confirmed this P24L substitution in at least twenty unrelated families worldwide, establishing a recurrent founder effect for the V1 head-domain variant (PMID:20923750).

The inheritance pattern is autosomal dominant, with at least eight additional affected relatives demonstrating segregation of heterozygous P24L or P25L mutations across pedigrees. The variant spectrum in EBS-MP is dominated by head-domain missense mutations (c.71C>T (p.Thr24Ile), c.74C>T (p.Pro25Leu)), with occasional rare frameshift alleles (e.g., c.1649del (p.Gly550AlafsTer?)) in the V2 domain.

Functional studies using in vitro assembly assays and keratinocyte transfection models have shown that P24L and related head-domain mutations exert a dominant-negative effect on 10-nm filament formation, mildly perturbing filament length and disrupting cytoskeletal organization under mechanical stress. These findings are concordant with the mild but persistent clinical phenotype of EBS-MP.

No conflicting evidence has been reported to date for the role of KRT5 in EBS-MP. The genetic and experimental data together support a strong gene–disease association and a dominant-negative mechanism of pathogenicity.

Key Take-Home: Screening for recurrent head-domain missense variants in KRT5 (notably c.71C>T (p.Thr24Ile)) is clinically valuable for the diagnosis and genetic counseling of EBS-MP.

References

• American journal of medical genetics • 1999 • Epidermolysis bullosa simplex with mottled pigmentation: clinical aspects and confirmation of the P24L mutation in the KRT5 gene in further patients. PMID:10494094
• Proceedings of the National Academy of Sciences of the United States of America • 1996 • The genetic basis of epidermolysis bullosa simplex with mottled pigmentation. PMID:8799157
• The Journal of investigative dermatology • 1997 • A mutation in the V1 domain of keratin 5 causes epidermolysis bullosa simplex with mottled pigmentation. PMID:9129237
• European journal of dermatology • 2010 • Epidermolysis bullosa simplex with mottled pigmentation - mutation analysis proved the diagnosis in a four-generation pedigree. PMID:20923750

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