Sutter, N. | Search bioRxiv

bioRxiv2026

Hailey-Hailey disease models identify synergistic therapeutic effects of MEK and ROCK inhibition

Hailey-Hailey disease (HHD) is a genetic skin blistering disorder lacking approved treatments despite linkage to ATP2C1 variants 25 years ago. Since knockout mice did not replicate HHD, we ablated ATP2C1 in human keratinocytes or chemically inhibited its encoded Golgi calcium pump SPCA1. In organotypic epidermis, SPCA1 deficiency or inhibition reproduced HHD pathology, disrupting desmosomal cadherins and severing cell-cell junctions, termed acantholysis. RNA sequencing of heterozygous cells identified dysregulation of actin and Rho GTPases along with EGF receptor signaling as potential pathogenic drivers. Accordingly, SPCA1-depleted organotypic epidermis and HHD biopsies exhibited cortical actin disorganization and hyper-phosphorylation of the Rho kinase (ROCK) target, myosin light chain. Rho activation was sufficient to induce acantholysis, while ROCK inhibition partially restored heterozygous keratinocyte cohesion. A fluorescent biosensor demonstrated ERK hyper-activation in heterozygous cells along with desmosomal cadherin mis-localization. Importantly, treating SPCA1-deficient keratinocyte sheets with MEK and ROCK inhibitors together fully restored their integrity. Our results show HHD blistering is driven by desmosome and cortical actin dysfunction that was mitigated by targeting MEK and ROCK with repurposed drugs, offering a viable treatment strategy. Moreover, our model provides a blueprint for replicating genetic epidermal disorders to delineate pathogenic mechanisms and vet therapeutics for other orphan skin diseases. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=199 SRC="FIGDIR/small/726679v1_ufig1.gif" ALT="Figure 1"> View larger version (57K): org.highwire.dtl.DTLVardef@b2de6aorg.highwire.dtl.DTLVardef@128411borg.highwire.dtl.DTLVardef@1ca760forg.highwire.dtl.DTLVardef@10cd6c7_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗

bioRxiv2019

Whole Genome Detection of Sequence and Structural Polymorphism in Six Diverse Horses

The domesticated horse has played a unique role in human history, serving not just as a source of animal protein, but also as a catalyst for long-distance migration and military conquest. As a result, the horse developed unique physiological adaptations to meet the demands of both their climatic environment and their relationship with man. Completed in 2009, the first domesticated horse reference genome assembly (EquCab 2.0) produced most of the publicly available genetic variations annotations in this species. Yet, there are around 400 geographically and physiologically diverse breeds of horse. To enrich the current collection of genetic variants in the horse, we sequenced whole genomes from six horses of six different breeds: an American Miniature, a Percheron, an Arabian, a Mangalarga Marchador, a Native Mongolian Chakouyi, and a Tennessee Walking Horse. Aside from extreme contrasts in body size, these breeds originate from diverse global locations and each possess unique adaptive physiology. A total of 1.3 billion reads were generated for the six horses with coverage between 15x to 24x per horse. After applying rigorous filtration, we identified and functionally annotated 8,128,658 Single Nucleotide Polymorphisms (SNPs), and 830,370 Insertions/Deletions (INDELs), as well as novel Copy Number Variations (CNVs) and Structural Variations (SVs). Our results revealed putatively functional variants including genes associated with size variation like ANKRD1 and HMGA1 in the very large Percheron and the ZFAT gene in the American Miniature horse. We detected a copy number gain in the Latherin gene that may be the result of evolutionary selection for thermoregulation by sweating, an important component of athleticism and heat tolerance. The newly discovered variants were formatted into user-friendly browser tracks and will provide a foundational database for future studies of the genetic underpinnings of diverse phenotypes within the horse. Author SummaryThe domesticated horse played a unique role in human history, serving not just as a source of dietary animal protein, but also as a catalyst for long-distance migration and military conquest. As a result, the horse developed unique physiological adaptations to meet the demands of both their climatic environment and their relationship with man. Although the completion of the horse reference genome yielded the discovery of many genetic variants, the remarkable diversity across breeds of horse calls for additional effort in quantification of the breadth of genetic polymorphism within this unique species. Here, we present genome re-sequencing and variant detection analysis for six horses belonging to geographically and physiologically diverse breeds. We identified and annotated not just single nucleotide polymorphisms (SNPs), but also large insertions and deletions (INDELs), copy number variations (CNVs) and structural variations (SVs). Our results illustrate novel sources of polymorphism and highlight potentially impactful variations for phenotypes of body size and conformation. We also detected a copy number gain in the Latherin gene that could be the result of an evolutionary selection for thermoregulation through sweating. Our newly discovered variants were formatted into easy-to-use tracks that can be easily accessed by researchers around the globe.

genomics↗