KRT14

Chr 17ADAR

keratin 14

Also known as: CK14, EBS1, EBS1A, EBS1B, EBS1C, EBS1D, EBS3, EBS4

NCBI Gene: 3861 ENSG00000186847 UniProt: P02533 OMIM: 148066

The protein forms heterotetramer complexes with keratin 5 to create intermediate filaments that comprise the cytoskeleton of epithelial cells, with the nonhelical tail domain promoting filament bundling and mechanical resilience. Mutations cause multiple forms of epidermolysis bullosa simplex (ranging from localized to severe generalized), dermatopathia pigmentosa reticularis, and Naegeli-Franceschetti-Jadassohn syndrome through dominant-negative mechanisms, with inheritance patterns that are typically autosomal dominant but can be autosomal recessive. The pathogenicity results from disrupted keratin filament structure and function, compromising epithelial cell integrity and leading to skin fragility and blistering.

OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

This gene encodes a member of the keratin family, the most diverse group of intermediate filaments. This gene product, a type I keratin, is usually found as a heterotetramer with two keratin 5 molecules, a type II keratin. Together they form the cytoskeleton of epithelial cells. Mutations in the genes for these keratins are associated with epidermolysis bullosa simplex. At least one pseudogene has been identified at 17p12-p11. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

MultiplemechanismAD/ARLOEUF 0.856 OMIM phenotypes

Clinical Summary— KRT14

⚡

Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.85LOEUF

pLI 0.000

Z-score 2.06

OE 0.48 (0.29–0.85)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.84Z-score

OE missense 0.86 (0.78–0.96)

250 obs / 290.0 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.48 (0.29–0.85)

0≤0.351.4

Missense OE?0.86 (0.78–0.96)

0≤0.61.4

Synonymous OE?1.15

0≤1.21.6

LoF obs/exp: 9 / 18.6Missense obs/exp: 250 / 290.0Syn Z: -1.34

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveKRT14-related Naegeli syndromeLOFAD

definitiveKRT14-related epidermolysis bullosa simplexLOFAR

definitiveKRT14-related epidermolysis bullosa simplex generalised severe (Dowling-Meara)DNAD

definitiveKRT14-related epidermolysis bullosa simplex generalised intermediate (Köbner)DNAD

definitiveKRT14-related epidermolysis bullosa simplex localised (Weber Cockayne)DNAD

This gene — mechanism propensity

0.96top 5%

GOF

0.93top 5%

LOF

0.1697th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative, gain-of-function and loss-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to dominant-negative as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

DNprediction above median · 1 literature citation

GOFprediction above median

LOF1 literature citation

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Literature Evidence

DNThe simplex form of EB is usually caused by dominantly inherited mutations in KRT5 or KRT14. These mutations result in the production of proteins with dominant-negative activity that disrupt polymerization of intermediate filaments in the basal keratinocyte layer and result in a weak epidermalderma1

LOFKRT14 haploinsufficiency results in increased susceptibility of keratinocytes to TNF-alpha-induced apoptosis and causes Naegeli-Franceschetti-Jadassohn syndrome.2

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

References