HMCN1 variants aggravate epidermolysis bullosa simplex phenotype

• Published in: The Journal of experimental medicine Vol. 222; no. 5
• Main Authors: Bergson, Shir, Sarig, Ofer, Giladi, Moshe, Mohamad, Janan, Mogezel-Salem, Mariana, Smorodinsky-Atias, Karina, Sade, Ofir, Manori, Bar, Assaf, Sari, Malovitski, Kiril, Feller, Yarden, Pavlovsky, Mor, Hainzl, Stefan, Kocher, Thomas, Hummel, Julia I., Eretz Kdosha, Noy, Khair, Lubna Gazi, Zauner, Roland, Pinon Hofbauer, Josefina, Shalom-Feuerstein, Ruby, Wally, Verena, Koller, Ulrich, Samuelov, Liat, Haitin, Yoni, Ashery, Uri, Rubinstein, Rotem, Sprecher, Eli
• Format: Journal Article
• Language: English
• Published: United States Rockefeller University Press 05.05.2025
• Subjects: Adolescent; Child; Epidermolysis Bullosa Simplex - genetics; Epidermolysis Bullosa Simplex - metabolism; Epidermolysis Bullosa Simplex - pathology; Female; Human Disease Genetics; Humans; Keratin-14 - genetics; Keratin-14 - metabolism; Male; Mutation - genetics; Phenotype; Protein Binding; Protein Stability; Skin - metabolism; Skin - pathology
• ISSN: 0022-1007; 1540-9538; 1540-9538
• DOI: 10.1084/jem.20240827

Epidermolysis bullosa simplex (EBS) refers to a heterogeneous group of inherited skin disorders characterized by blister formation within the basal cell layer. The disease is characterized by marked variations in phenotype severity, suggesting co-inheritance of genetic modifiers. We identified three deleterious variants in HMCN1 that co-segregated with a more severe phenotype in a group of 20 individuals with EBS caused by mutations in KRT14, encoding keratin 14 (K14). HMCN1 codes for hemicentin-1. Protein modeling, molecular dynamics simulations, and functional experiments showed that all three HMCN1 variants disrupt protein stability. Hemicentin-1 was found to be expressed in human skin above the BMZ. Using yeast-2-hybrid, co-immunoprecipitation, and proximity ligation assays, we found that hemicentin-1 binds K14. Three-dimensional skin equivalents grown from hemicentin-1–deficient cells were found to spontaneously develop subepidermal blisters, and HMCN1 downregulation was found to reduce keratin intermediate filament formation. In conclusion, hemicentin-1 binds K14 and contributes to BMZ stability, which explains the fact that deleterious HMCN1 variants co-segregate with a more severe phenotype in KRT14-associated EBS.