Tmem79/Matt is the matted mouse gene and is a predisposing gene for atopic dermatitis in human subjects

Abstract

BackgroundAtopic dermatitis (AD) is a major inflammatory condition of the skin caused by inherited skin barrier deficiency, with mutations in the filaggrin gene predisposing to development of AD. Support for barrier deficiency initiating AD came from flaky tail mice, which have a frameshift mutation in Flg and also carry an unknown gene, matted, causing a matted hair phenotype.ObjectiveWe sought to identify the matted mutant gene in mice and further define whether mutations in the human gene were associated with AD.MethodsA mouse genetics approach was used to separate the matted and Flg mutations to produce congenic single-mutant strains for genetic and immunologic analysis. Next-generation sequencing was used to identify the matted gene. Five independently recruited AD case collections were analyzed to define associations between single nucleotide polymorphisms (SNPs) in the human gene and AD.ResultsThe matted phenotype in flaky tail mice is due to a mutation in the Tmem79/Matt gene, with no expression of the encoded protein mattrin in the skin of mutant mice. Mattft mice spontaneously have dermatitis and atopy caused by a defective skin barrier, with mutant mice having systemic sensitization after cutaneous challenge with house dust mite allergens. Meta-analysis of 4,245 AD cases and 10,558 population-matched control subjects showed that a missense SNP, rs6694514, in the human MATT gene has a small but significant association with AD.ConclusionIn mice mutations in Matt cause a defective skin barrier and spontaneous dermatitis and atopy. A common SNP in MATT has an association with AD in human subjects.

Epidermal tight junctions in health and disease

“…In the flaky tail mouse, which has a spontaneous mutation in FLG (similar to the mutations found in subjects with IV) and a matted tail mutation (Tmem79/matt) investigators have observed a reduction in occludin (at both mRNA and protein level). 103 These investigators also observed reductions in occludin (mRNA and protein levels) in HaCaT cells transfected with FLG-siRNA and highlighted that loricrin and the silent mating type information regulation 2 homolog 1 (SIRT1) might be part of the signaling pathway that links FLG and occludin. 104 However, it cannot be ruled out that the Tmem79/matt mutation may contribute to changes of occludin in the flaky tail mouse.…”

Topical steroids and emollients in atopic eczema – which should be applied first?

“…More recently, cohort studies investigating mutations of the filaggrin gene in adults and children, have demonstrated differences between ethnic groups and in responsiveness to treatment (Margolis et al, 2012). Whilst further gene polymorphisms have been linked to abnormal immune responses in AE (Saunders et al, 2013). Ultimately eczematous skin is unable to provide the protective barrier function essential for health.…”

Deciphering the complexities of atopic dermatitis: Shifting paradigms in treatment approaches

“…It was originally thought that the filaggrin deficiency in Flaky Tail mice explained the propensity of these mice to develop AD. Surprisingly, the derivation of genetically engineered filaggrin-deficient mice that were free of the ma gene mutation, were found to display impaired barrier function but to lack the propensity to spontaneously develop eczema (37,38). The matted phenotype in flaky tail mice was found to be due to a loss-of-function mutation in the Tmem79 gene.…”

“…Interestingly, Tmem79 encodes lamellar granules that are required for processing of filaggin, lipids, proteases and antimicrobial peptides (22). Saunders et al (37) has also found that a single nucleotide polymorphism in the human TMEM79 gene confers a significant risk for AD in humans, even when controlling for the effect of FLG mutations, suggesting both genes are involved in AD and the need for genegene interactions.…”