Ichthyosis Hystrix of Curth-Macklin (IH-CM) is a rare manifestation of epidermolytic ichthyosis (EI) that is characterised by generalised spiky or verrucous hyperkeratosis. The disorder is further distinguished by the presence of binucleated cells in the affected skin, whereas epidermolysis and clumping of tonofilaments, as seen in EI, are absent. While IH-CM is associated with mutations in the keratin 1 (KRT1) gene, reports to date have indicated that mutations in the KRT1 gene result in an aberrant and truncated protein tail, essentially affecting the function of the V2 domain. Here, we studied a female sporadic patient who was born with diffused erythrodermic hyperkeratosis and who presented at the age of 13 months with an intense and widespread hyperkeratosis with a papillomatous appearance and typical palmoplantar keratoderma. Genetic analysis demonstrated a “de novo” mutation in the keratin 10 gene (KRT10) consisting of a three-base-pair deletion, resulting in the substitution of amino acids p.Glu445 and p.Ile446 by Asp at the end of the 2B domain of the protein. We performed structural and functional studies showing that this mutation modifies the structure of the paired 2B and V2 K1/10 domains, leading to the disease phenotype. Our results highlight the importance and complexity of the KRT1/10 V2 domain in keratin dimer formation and the potential consequences of its alteration.
ASJC Scopus subject areas
- Biochemistry, Genetics and Molecular Biology(all)
- Agricultural and Biological Sciences(all)