Disease-associated KIF3A variants alter gene methylation and expression impacting skin barrier and atopic dermatitis risk
Mariana L. Stevens, Zhonghua Zhang, Elisabet Johansson, Samriddha Ray, Amrita Jagpal, Brandy Ruff, Arjun Kothari, Hua He, Lisa J. Martin, Hong Ji, Kathryn A. Wikenheiser‐Brokamp, Matthew T. Weirauch, Dorothy M. Supp, Jocelyn M. Biagini Myers, Gurjit K. Khurana Hershey
Abstract
Abstract 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. Kif3a K14 ∆ / ∆ 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.