KRT4 – Hereditary Mucosal Leukokeratosis

Hereditary mucosal leukokeratosis is a rare disorder characterized by white, spongy plaques on the oral mucosa. Several independent case reports have documented mutations in KRT4 as the underlying cause, with clinical presentations that include diffuse oral lesions and histopathologic features such as epithelial thickening and vacuolization (PMID:10652003).

Multiple studies have identified heterozygous mutations in KRT4 in affected individuals. For example, a heterozygous missense mutation, c.1303G>A (p.Glu435Lys), has been reported and is representative of the type of alterations seen in these patients (PMID:12828738). This variant, among others, provides robust genetic evidence for the involvement of KRT4 in this disorder.

The disorder follows an autosomal dominant inheritance pattern, and segregation analyses in several families have demonstrated co‐segregation of the mutated allele with the disease phenotype. In aggregate, family studies report at least seven additional affected relatives carrying the mutant allele, further reinforcing the genetic link (PMID:23182699). The variant spectrum primarily comprises missense and small insertion mutations affecting critical regions such as the helix initiation motif.

Functional assessments, including histopathologic evaluations and in silico predictions, indicate that these pathogenic variants disrupt the assembly of intermediate filaments. Such disruption is congruent with the clinical features observed in patients and provides moderate experimental support for the impact of these alterations on protein function (PMID:10652003).

Although a few studies have investigated overlapping phenotypes with other keratin disorders, the bulk of the evidence consistently supports a specific association between KRT4 mutations and hereditary mucosal leukokeratosis. No significant conflicting data have emerged that would detract from this relationship.

In summary, the convergence of genetic and functional evidence strongly supports the association between KRT4 mutations and hereditary mucosal leukokeratosis. This integrated insight aids diagnostic decision‑making and provides a basis for targeted genetic screening, underscoring the clinical utility of incorporating KRT4 mutation analysis in the evaluation of patients with oral white lesions.

References

• The Journal of Investigative Dermatology • 2000 • A glutamine insertion in the 1A alpha helical domain of the keratin 4 gene in a familial case of white sponge nevus PMID:10652003
• The British Journal of Dermatology • 2003 • A novel mutation in the keratin 4 gene causing white sponge naevus PMID:12828738
• International Journal of Oral and Maxillofacial Surgery • 2013 • Mutation of keratin 4 gene causing white sponge nevus in a Japanese family PMID:23182699
• Journal of Oral Pathology & Medicine • 2018 • Mutations in the genes for keratin-4 and keratin-13 in Swedish patients with white sponge nevus PMID:29047160

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