Tissue-specific contributions of <i>Tmem79</i> to atopic dermatitis and mast cell-mediated histaminergic itch.
Emrick JJ
et al.
Proc Natl Acad Sci U S A 2018 Dec;115(51)E12091-E12100
Emrick JJ, Mathur A, Wei J, Gracheva EO, Gronert K, Rosenblum MD, Julius D.
Proc Natl Acad Sci U S A 2018 Dec;115(51)E12091-E12100
Abstract: Atopic dermatitis (AD) is the most common skin disease in children. It is characterized by relapsing inflammation, skin-barrier defects, and intractable itch. However, the pathophysiology of itch in AD remains enigmatic. Here, we examine the contribution of <i>Tmem79</i>, an orphan transmembrane protein linked to AD in both mice and humans. We show that <i>Tmem79</i> is expressed by both keratinocytes and sensory neurons, but that loss of keratinocytic <i>Tmem79</i> is sufficient to elicit robust scratching. <i>Tmem79</i><sup><i>-/-</i></sup> mice demonstrate an accumulation of dermal mast cells, which are diminished following chronic treatment with cyclooxygenase inhibitors and an EP3 receptor antagonist. In <i>Tmem79</i><sup><i>-/-</i></sup> mice, mast cell degranulation produces histaminergic itch in a histamine receptor 1/histamine receptor 4 (H4R/H1R)-dependent manner that may involve activation of TRPV1<sup>-</sup> afferents. TMEM79 has limited sequence homology to a family of microsomal glutathione transferases and confers protection from cellular accumulation of damaging reactive species, and may thus play a role in regulating oxidative stress. In any case, mechanistic insights from this model suggest that therapeutics targeting PGE<sub>2</sub> and/or H1R/H4R histaminergic signaling pathways may represent useful avenues to treat <i>Tmem79</i>-associated AD itch. Our findings suggest that individuals with mutations in <i>Tmem79</i> develop AD due to the loss of protection from oxidative stress.
Tmem79/Matt is the matted mouse gene and is a predisposing gene for atopic dermatitis in human subjects.
Saunders SP
et al.
J Allergy Clin Immunol 2013 Nov;132(5)1121-1129
Saunders SP, Goh CS, Brown SJ, Palmer CN, Porter RM, Cole C, Campbell LE, Gierlinski M, Barton GJ, Schneider G, Balmain A, Prescott AR, Weidinger S, Baurecht H, Kabesch M, Gieger C, Lee YA, Tavendale R, Mukhopadhyay S, Turner SW, Madhok VB, Sullivan FM, Relton C, Burn J, Meggitt S, Smith CH, Allen MA, Barker JN, Reynolds NJ, Cordell HJ, Irvine AD, McLean WH, Sandilands A, Fallon PG.
J Allergy Clin Immunol 2013 Nov;132(5)1121-1129
Abstract: <h4>Background</h4>Atopic 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.<h4>Objective</h4>We sought to identify the matted mutant gene in mice and further define whether mutations in the human gene were associated with AD.<h4>Methods</h4>A 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.<h4>Results</h4>The 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. Matt(ft) 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, rs6684514, [corrected] in the human MATT gene has a small but significant association with AD.<h4>Conclusion</h4>In 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.