Epidermolytic palmoplantar keratoderma caused by activation of a cryptic splice site inKRT9

Abstract

Summary Epidermolytic palmoplantar keratoderma (EPPK) is caused by mutations in KRT9 and less often, KRT1. All known mutations in KRT9 have been found in regions of the gene encoding the conserved central α‐helix rod domain. In the present study, we investigated the molecular basis of EPPK in a patient of Ashkenazi Jewish origin. The patient was found to carry a novel missense mutation in KRT9, resulting in the substitution of a poorly conserved leucine for valine at position 11 of the amino acid sequence. Despite its unusual location, the mutation was shown to be pathogenic through activation of a cryptic donor splice site, resulting in the deletion of 162 amino acids. The present data indicate the need to screen keratin genes in their entirety, as mutations altering domains of lesser functional importance may exert their deleterious effect at the transcriptional level.

Palmoplantar Keratoderma: A Molecular Genetic Analysis of Family Cases

“…We carried out direct Sanger sequencing for the KRT9 gene from locus 17q21. As a result, we detected a previously described pathogenic variant in all family members with keratoderma: KRT9 (NM_000226.4): c.31T>G (p.(Leu11Val)) [ 14 ]. This variant was not detected in healthy family members, was not registered in gnomAD, and was not present in 1335 exomes of Russian patients from the “RuExac” database.…”

“…The patient did not have hyperhidrosis or hair/nail abnormalities. The cause of the disease was the same as in the LPG3 family: a KRT9 (NM_000226.4): c.31T>G (p.(Leu11Val)) mutation [ 14 ].…”