Palmoplantar keratoderma (PPK) represents a heterogeneous group of disorders characterized by hyperkeratosis of the palms and soles. Epidermolytic palmoplantar keratoderma (EPPK) is typically caused by variations in KRT9 or KRT1 genes. However, growing evidence suggests that defects in desmosomal genes, particularly desmoplakin (DSP), may underlie atypical variants. We report a 17-year-old girl with a 10-year history of yellowish, hyperkeratotic plaques with greasy scales on the dorsal hands, soles, and axillae. Histopathology revealed hyperkeratosis, parakeratosis, and acantholysis. Whole-exome sequencing (WES) identified a novel heterozygous frameshift variation in DSP (c.6218_6219dup, p. Ala2074Ter), confirmed by Sanger sequencing. This is the first report of an atypical EPPK caused by a DSP frameshift variation in the C-terminal domain, expanding the genotypic and phenotypic spectrum of PPK. The variant was absent from the gnomAD database. Functional studies demonstrated significant downregulation of adhesion molecules (CDH1, JUP, and CTNNA1) upon DSP knockdown, suggesting impaired desmosome-keratin anchoring as the pathogenic mechanism. This case reveals that DSP C-terminal domain variations can cause a new subtype of EPPK, providing new insights into PPK diagnosis and treatment.

Palmoplantar skin is structurally and molecularly distinct from other body sites. Notably, the type 1 keratin 9 ( KRT9 /K9) is exclusively expressed in palmoplantar epidermis. Mutations in KRT9 /K9 are causative for epidermolytic palmoplantar keratoderma (EPPK), a genetic disorder typified by palmoplantar keratoderma. Surprisingly little is known about the ontogeny, regulation and significance of Krt9 /K9. Here we characterize the regulation of Krt9 /K9 in postnatal palmoplantar epidermis and uncover a novel role of K9 in modulating YAP1 signaling. Expression of Krt9/ K9 rises dramatically post-birth, following a transient induction of the stress-related keratin 16 (Krt16/ K16 ). Krt9 null mice exhibit elevated K16 and aberrant nuclear-localized YAP1 by postnatal day 3. K9 interacts with 14-3-3σ to sequesters YAP1 in the cytoplasm, while EPPK-causing pathogenic variants impair these properties. Inhibition of YAP1 in vivo ameliorates palmoplantar keratoderma in Krt9 null mice. These findings provide novel insight into the adaptation of palmoplantar skin and suggest new therapeutic avenues for diseases featuring PPKs. Expression of Keratin 9 ( Krt9 /K9), a keratin specific to the thicker epidermis of palmoplantar skin, increases dramatically early after birth Onset of Krt9 /K9 expression follows, and is dependent on, K16, a stress-responsive keratin Krt9 null mice have aberrant nuclear YAP1 localization in differentiating keratinocytes of footpad skin Pharmacological or genetic inhibition of YAP1 rescues hyperkeratosis in Krt9 null mice Keratins play a crucial role in regulating differentiation and homeostasis in skin epithelia.

iRhoms are pseudoprotease members of the rhomboid-like superfamily and are cardinal regulators of inflammatory and growth factor signaling; they function primarily by recognizing transmembrane domains of their clients. Here, we report a mechanistically distinct nuclear function of iRhoms, showing that both human and mouse iRhom2 are non-canonical substrates of signal peptidase complex (SPC), the protease that removes signal peptides from secreted proteins. Cleavage of iRhom2 generates an N-terminal fragment that enters the nucleus and modifies the transcriptome, in part by binding C-terminal binding proteins (CtBPs). The biological significance of nuclear iRhom2 is indicated by elevated levels in skin biopsies of patients with psoriasis, tylosis with oesophageal cancer (TOC), and non-epidermolytic palmoplantar keratoderma (NEPPK); increased iRhom2 cleavage in a keratinocyte model of psoriasis; and nuclear iRhom2 promoting proliferation of keratinocytes. Overall, this work identifies an unexpected SPC-dependent ER-to-nucleus signaling pathway and demonstrates that iRhoms can mediate nuclear signaling.

Keratosis palmoplantaris striata type I (SPPK-I) is a rare autosomal-dominant type of hereditary epidermolytic palmoplantar keratoderma, which can be caused by mutations in desmoglein-1 (DSG-1). Patients suffer from hyperkeratotic plaques and painful palmoplantar fissures. Unfortunately, treatment options including salicylic vaseline, topical corticosteroids, phototherapy, and retinoids are inefficient. Hereditary palmoplantar keratodermas (PPKs) represent a heterogeneous group of rare skin disorders with epidermal palmoplantar hyperkeratosis. Mutations in the desmoglein 1 gene (DSG1), a transmembrane glycoprotein, have been reported primarily in striate PPKs. We report a patient with keratosis palmoplantaris striata type I (SPPK-I) with a specific pathogenic variant [c.349C>T, p.(Arg117*)] in DSG1. Despite increased understanding, effective treatment options for PPK, including SPPK-I, remain limited.