Identification and characterization of the gene responsible for the matted mouse phenotype

Abstract

The skin barrier plays an essential role in protecting the body from external assaults and maintaining homeostasis. The differentiation of keratinocytes into toughened corneocytes begins in the basal layer of the epidermis and culminates in the formation of the stratum corneum (SC). Corneocytes are terminally differentiated cells which form a protective shield consisting of insoluble structural proteins cross-linked to the lipid envelope of the cornified cell envelope. In recent years, many molecular participants behind the extensive remodeling of the epidermis have been uncovered, and a spectrum of epidermal diseases have been shown to be associated with mutations coding for structural or enzymatic proteins involved in the complex processes of differentiation. However, genetic determinants for many epidermal barrier disorders are still unknown. The work in this thesis focuses on identifying the gene responsible for the phenotype of the ^ma/maMatt (matted) mouse, which was first documented in 1957. To hunt this elusive gene down, extensive mapping of the murine epidermal differentiation complex (EDC) was carried out and the gene identified as transmembrane 79 (Tmem79). Further work characterizing the human ortholog of TMEM79 showed that the protein localized to the membranes of lamellar granules (LG) in keratinocytes in the upper granular layers. Various human populations with skin diseases were screened, but no predisposition was identified between TMEM79 and allergic phenotypes.
In conclusion, Tmem79 is responsible for the phenotype seen in the ^ma/maMatt mouse, leading to spontaneous dermatitis due to a skin barrier defect. This novel gene encodes for a protein that is involved in desquamation of cornified layers, where an aberrant TMEM79 results in dysfunction LG transport/secretion.