Disease-associated KIF3A variants alter gene methylation and expression impacting skin barrier and atopic dermatitis risk.

Single nucleotide polymorphisms (SNPs) in the gene encoding kinesin family member 3A, KIF3A, have been associated with atopic dermatitis (AD), a chronic inflammatory skin disorder. We find that KIF3A SNP rs11740584 and rs2299007 risk alleles create cytosine-phosphate-guanine sites, which are highly methylated and result in lower KIF3A expression, and this methylation is associated with increased transepidermal water loss (TEWL) in risk allele carriers. Kif3aK14∆/∆ mice have increased TEWL, disrupted junctional proteins, and increased susceptibility to develop AD. Thus, KIF3A is required for skin barrier homeostasis whereby decreased KIF3A skin expression causes disrupted skin barrier function and promotes development of AD. Genetic variants in KIF3A are associated with atopic dermatitis (AD). Here, the authors identify two AD-risk alleles that show high methylation resulting in lower KIF3A expression. Mice with epidermis-specific loss of Kif3a show disrupted skin barrier homeostasis and increased AD susceptibility.