A Keratin 9 Gene Mutation (Met156Thr) In A Chinese Pedigree With Epidermolytic Palmoplantar Keratoderma

BackgroundEpidermolytic palmoplantar keratoderma (EPPK) was an autosomal dominant disorder caused by mutation in the keratin 9 gene on chromosome 17q12-q21. It was characterized by marked hyperkeratosis on the surface of palms and soles, and histologically by epidermolysis in suprabasal layers of the epidermis. EKKP had the tendency to develop breast or ovarian cancer. The mutation of KRT9 gene destroyed the formation of intermediate filament network in the cells. According to the pedigrees which had been reported, exonl was a hot spot of mutation.ObjectiveTo analyze the gene mutation of KRT9 gene in a 5-generation pedigree with EPPK, involving 11 affected individuals (9 males and 2 females). To find the relationship between genotype and phenotype by searching the cases in the Human Intermediate Filament Database.Materials and MethodsThe pedigree was a large 5-generation kindred with EPPK from Meizhou, Guangdong province. After obtaining informed consent, mutation analyses of genomic DNA were performed in 7 affected and 4 unaffected individuals. Besides, twenty unrelated controls were randomly selected.Results1. EPPK had genetic heterogeneity, even in the same family. 2. All affected individuals carried a heterozygous T to C substitution at 467 in KRT9 exon 1, resulting in the substitution of threonine for methionine at 156. None of the unaffected individuals in the family or the 20 controls carried this mutation.3. The KRT9 gene-99 G/A polymorphism was detected.4. As the number of cases was not enough, the relationship between phenotype and genotype was not very clear.Conclusion1. The mutation M156T which was found in keratin 9 gene was the disease-causing mutation in the family with epidermolytic palmoplantar keratoderma.2. The missense mutation (Met156Thr) in the 1A domain segment was confirmed as a hot spot in the Chinese population.3. The missense mutations did not change the length of peptide, but the transition changed the nature of keratin 9 peptide (from hydrophobic amino acid to polar amino acid) and destroyed the coiled-coil structure, then consequently disrupted the stability of the cytoskeleton in the epithelial cells.4. The efficiency can be improved by screening hot spot mutation region. According to the clinical phenotype and pathological features, the initial diagnosis was EPPK, but there was no mutation of KRT9. In this situation, KRT1, KRT10, and KRT16 should be considered as candidate.