Functional Conservation of Gsdma Cluster Genes Specifically Duplicated in the Mouse Genome

Abstract

Mouse Gasdermin A3 (Gsdma3) is the causative gene for dominant skin mutations exhibitingalopecia. Mouse has two other Gsdma3-related genes, Gsdma and Gsdma2, whereas human and rat haveonly one related gene. To date, no skin mutation has been reported for human GSDMA and rat Gsdma aswell as mouse Gsdma and Gsdma2. Therefore, it is possible that only Gsdma3 has gain-of-function typemutations to cause dominant skin phenotype. To elucidate functional divergence among the Gsdmarelatedgenes in mice, and to infer the function of the human and rat orthologs, we examined in vivofunction of mouse Gsdma by generating Gsdma knockout mice and transgenic mice that overexpress wildtypeGsdma or Gsdma harboring a point mutation (Alanine339Threonine). The Gsdma knockout miceshows no visible phenotype, indicating that Gsdma is not essential for differentiation of epidermal cellsand maintenance of the hair cycle, and that Gsdma is expressed specifically both in the inner root sheath ofhair follicles and in suprabasal cell layers, whereas Gsdma3 is expressed only in suprabasal layers. Bycontrast, both types of the transgenic mice exhibited epidermal hyperplasia resembling the Gsdma3 mutations,although the phenotype depended on the genetic background. These results indicate that the mouseGsdma and Gsdma3 genes share common function to regulate epithelial maintenance and/or homeostasis,and suggest that the function of human GSDMA and rat Gsdma, which are orthologs of mouse Gsdma, isconserved as well. © 2013 Tanaka et al.