KRT12 – Meesmann Corneal Dystrophy

Meesmann corneal dystrophy (MECD) is a rare, autosomal dominant disorder characterized by the presence of intraepithelial corneal microcysts, leading to symptoms such as photophobia and ocular irritation. Multiple independent clinical investigations spanning over two decades have implicated mutations in KRT12 as causative for the disease (PMID:32308613, PMID:9399908).

Genetic evidence originates from several case reports and multi‐patient cohort studies that demonstrate heterozygous missense mutations segregating with the disease phenotype in affected families. In one study, a Vietnamese pedigree exhibited a novel heterozygous mutation, c.1273G>A (p.Glu425Lys), which was identified in multiple affected probands and segregated with the disease (PMID:32308613). Additional reports have described similar missense mutations in KRT12 confirming the genetic etiology of MECD.

The genetic data are underscored by evidence of autosomal dominant inheritance, with segregation observed in several affected relatives (approximately 7 additional individuals across families). The recurrent identification of KRT12 mutations across independent studies consolidates its role as the disease‐causing gene in MECD (PMID:9399908).

Beyond the clinical genetic findings, functional studies have strongly supported the pathogenicity of these variants. In vitro assays, including allele‐specific siRNA experiments, and in vivo mouse models have demonstrated that mutant KRT12 proteins disrupt keratin filament assembly and induce cellular stress responses, consistent with the dominant‐negative mechanism observed in patients (PMID:23233254, PMID:26758872).

Integrating the genetic and experimental data, the evidence strongly supports a definitive link between KRT12 mutations and MECD. The recurrent identification of pathogenic variants in multiple unrelated probands, combined with robust functional assessments, confirms the clinical validity of this gene‐disease association. Although additional variants and experimental data exist, the accumulated evidence exceeds the ClinGen scoring maximum and offers clear diagnostic utility.

Key take‑home message: Screening for KRT12 mutations, such as c.1273G>A (p.Glu425Lys), provides high confidence for the diagnosis and management of MECD.

References

• Case reports in ophthalmology • 2020 • Identification of a Novel Missense KRT12 Mutation in a Vietnamese Family with Meesmann Corneal Dystrophy PMID:32308613
• PloS One • 2011 • Development of allele‑specific therapeutic siRNA in Meesmann epithelial corneal dystrophy PMID:22174841
• American journal of human genetics • 1997 • Isolation and chromosomal localization of a cornea‑specific human keratin 12 gene and detection of four mutations in Meesmann corneal epithelial dystrophy PMID:9399908
• Investigative ophthalmology & visual science • 2013 • Allele‑specific siRNA silencing for the common keratin 12 founder mutation in Meesmann epithelial corneal dystrophy PMID:23233254
• Human molecular genetics • 2016 • Keratin 12 missense mutation induces the unfolded protein response and apoptosis in Meesmann epithelial corneal dystrophy PMID:26758872
• Molecular vision • 2015 • Identification of presumed pathogenic KRT3 and KRT12 gene mutations associated with Meesmann corneal dystrophy PMID:26788030

Evidence Based Scoring (AI generated)