<i>HMCN1</i> variants aggravate epidermolysis bullosa simplex phenotype
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.
Authors
- Verena Wally (ORCID: https://orcid.org/0000-0001-8705-3890)
- Uri Ashery (ORCID: https://orcid.org/0000-0001-6338-7888)
- Stefan Hainzl (ORCID: https://orcid.org/0000-0001-6542-0039)
- Janan Mohamad (ORCID: https://orcid.org/0000-0002-9849-7566)
- Josefina Piñón Hofbauer (ORCID: https://orcid.org/0000-0002-8558-9031)
- Ofer Sarig (ORCID: https://orcid.org/0000-0003-2987-2091)
- Rotem Rubinstein (ORCID: https://orcid.org/0000-0003-3657-5984)
- Karina Smorodinsky-Atias (ORCID: https://orcid.org/0000-0002-5952-2650)
- Ruby Shalom‐Feuerstein (ORCID: https://orcid.org/0000-0002-8016-2290)
- Shir Bergson (ORCID: https://orcid.org/0000-0002-7197-8837)
- Ulrich Koller (ORCID: https://orcid.org/0000-0002-6285-1789)
- Eli Sprecher (ORCID: https://orcid.org/0000-0002-4093-1032)
- Kiril Malovitski (ORCID: https://orcid.org/0000-0002-4171-6668)
- Roland Zauner (ORCID: https://orcid.org/0000-0003-0590-3877)
- Noy Eretz Kdosha
- Bar Manori (ORCID: https://orcid.org/0000-0003-1414-0939)
- Yoni Haitin (ORCID: https://orcid.org/0000-0002-1648-6792)
- Yarden Feller (ORCID: https://orcid.org/0000-0002-0299-3304)
- Julia Illmer (ORCID: https://orcid.org/0000-0002-8305-6135)
- Liat Samuelov (ORCID: https://orcid.org/0009-0009-6498-9755)
- Sari Assaf (ORCID: https://orcid.org/0000-0002-5574-4918)
- Moshe Giladi (ORCID: https://orcid.org/0000-0002-8589-6920)
- Ofir Sade (ORCID: https://orcid.org/0009-0004-5849-782X)
- Thomas Köcher (ORCID: https://orcid.org/0000-0002-3424-3049)
- Mor Pavlovsky
- Lubna Gazi Khair
- Mariana Mogezel-Salem (ORCID: https://orcid.org/0009-0005-7277-2354)
Institutions
- Tel Aviv University (IL)
- Technion – Israel Institute of Technology (IL)
- Paracelsus Medical University (AT)
- EB House Austria (AT)
Publication Details
- Journal
- The Journal of Experimental Medicine
- Published
- 2025-02-20
- DOI
- https://doi.org/10.1084/jem.20240827
- Citations
- 5
- Primary Topic
- Skin and Cellular Biology Research
- Type
- article
- Field-Weighted Citation Impact
- 5.76
Funders
- Austrian Science Fund
- Israel Science Foundation
- Paracelsus Medizinische Privatuniversität
- Debra International