KRT14 – epidermolysis bullosa simplex

Epidermolysis bullosa simplex (EBS) is an inherited blistering skin disorder caused by mechanical stress–induced intraepidermal cleavage of basal keratinocytes. The type I keratin gene KRT14 encodes keratin 14, which heterodimerizes with keratin 5 to form the intermediate filament network essential for epidermal integrity. Mutations in KRT14 compromise filament assembly and confer cytolysis in basal cells under minor trauma.

KRT14-related EBS is predominantly autosomal dominant, with rare autosomal recessive presentations in complete loss-of-function alleles. In a cohort of 76 unrelated probands, sequencing identified KRT14 variants in 57 cases (41 distinct mutations), including missense, nonsense, frameshift, and splice-site changes (PMID:21375516). Segregation analysis in multiple multigenerational families and 37% de novo occurrence substantiate a dominant-negative mechanism.

A recurrent hotspot at codon 125 (c.373C>T (p.Arg125Cys)) accounts for ~40% of Dowling-Meara EBS cases; this variant cosegregates with disease in at least two families (LOD 3.29) and appears in sporadic patients (PMID:7688405). Other helix initiation peptide variants (e.g., p.Arg125His, p.Met119Thr) similarly disrupt keratin pairing and intermediate filament stability.

Functional assays demonstrate that K14 p.Arg125Cys and related mutants exert dominant-negative effects, causing keratin network collapse in transfected keratinocytes and impaired filament elongation in vitro (PMID:1717157). In contrast, homozygous null mutations (c.92del (p.Ile31fs)) abolish K14 expression yet produce milder recessive phenotypes, highlighting haploinsufficiency versus dominant-negative pathology (PMID:10971341).

Non-keratin modifiers (e.g., KLHL24, DST) may influence disease severity, but primary pathogenesis stems from KRT14 perturbations. Decades of consistent genetic, segregation, and functional data provide definitive evidence for KRT14 in EBS.

Key Take-home: Targeted sequencing of KRT14 helix boundary motifs, particularly codon 125, is clinically actionable for precise diagnosis, prognostication, and genetic counseling in EBS.

References

• The British Journal of Dermatology • 2011 • Mutations in KRT5 and KRT14 cause epidermolysis bullosa simplex in 75% of the patients PMID:21375516
• The Journal of Investigative Dermatology • 1993 • A keratin 14 mutational hot spot for epidermolysis bullosa simplex, Dowling-Meara: implications for diagnosis PMID:7688405
• Cell • 1991 • Point mutations in human keratin 14 genes of epidermolysis bullosa simplex patients: genetic and functional analyses PMID:1717157
• The British Journal of Dermatology • 2000 • A keratin 14 'knockout' mutation in recessive epidermolysis bullosa simplex resulting in less severe disease PMID:10971341

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