The Molecular Pathology of Progressive Symmetric Erythrokeratoderma: A Frameshift Mutation in the Loricrin Gene and Perturbations in the Cornified Cell Envelope

Abstract

The erythrokeratodermas (EKs) are a group of disorders characterized by erythematous plaques associated with variable features that include palmoplantar keratoderma. One type of EK is known as "progressive symmetric erythrokeratoderma" (PSEK). We studied members of a family of Japanese origin in which the index case with PSEK had had well-demarcated nonmigratory erythematous plaques on her extremities since birth. Sequence determination of the loricrin gene revealed an insertion of a C following nucleotide 709. The mutation results in a frameshift that changes the terminal 91 amino acids in the wild-type polypeptide into missense amino acids and adds 65 additional residues. This further implicates loricrin defects in the pathogenesis of disorders with palmoplantar keratoderma and pseudoainhum.

Bricks and mortar of the epidermal barrier

“…Frameshift mutations, resulting in loss of key glutamine and lysine residues for cross-linking, and expression of an aberrantly highly positively charged protein which accumulates in the nucleus instead, cause the autosomal dominant diseases Vo h w i n k e l 's k e r a t o d e r m a (keratoderma hereditaria mutilans (Vohwinkel, 1929;Gibbs and Frank, 1966;Korge et al, 1997;Lam et al, 1997) or progressive symmetric erythrokeratoderma ( I s h i d a - Yamamoto et al, 1997). In these diseases the CE i s thinner than normal and contains less loricrin (IshidaYamamoto et al, 1997;Korge et al, 1997;Lam et al, 1997). Patients with Vohwinkel's keratoderma have diff u s e palmoplantar hyperkeratosis with small "honeycomb" depressions and progressively develop constricting bands on their fingers.…”

Gene Targeting of Envoplakin, a Cytoskeletal Linker Protein and Precursor of the Epidermal Cornified Envelope

“…This correlated with a slight delay in barrier acquisition during embryonic development. We conclude that although envoplakin is part of the scaffolding on which the cornified envelope is assembled, it is not essential for envelope formation or epidermal barrier function.The functional endpoint of epidermal differentiation is assembly of the cornified envelope (CE), a covalently crosslinked protein layer that is deposited at the cytoplasmic face of the plasma membrane and forms a barrier between the living cell layers of the skin and the outside environment (16,26,27,35). The importance of the epidermal barrier is highlighted by the phenotype of mice which lack the gene for transglutaminase 1 (25), the key enzyme responsible for the cross-linking of envelope precursor proteins, in which a failure in cornified envelope assembly leads to excessive transepidermal water loss and neonatal lethality.…”

Progressive Symmetric Erythrokeratoderma. First case reported in the Dominican Republic

“…These overlapping characteristics have led some authors to propose the alternate term "EKV et progressiva" [7]. The molecular basis of PSE has not been clearly elucidated, Ishida et al reported mutations in the loricrine gene [6] which codifies for loricrin, a major structural component of the cornified cell envelope of the epidermis, which participates in the formation of keratohyalin granules; however similar mutations have not been found by other authors [4]. More studies are needed to clarify the molecular basis of this entity.…”

“…It usually develops during early childhood [3] as fixed and slowly progressive erythematous and hyperkeratotic plaques distributed symmetrically over the trunk, knees, elbows, dorsal surfaces of the hands and feet, and sometimes affecting also the face, palms and soles [4,5]. Despite that molecular basis of PSEK has not yet been established, there are reports of mutations in the loricrin gene [4,6]. As far as we are aware we report the first case of PSEK in the Dominican Republic.…”